ArticleLiterature Review

The Dawn Phenomenon Revisited: Implications for Diabetes Therapy

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

To summarize current data on the magnitude, prevalence, variability, pathogenesis, and management of the dawn phenomenon in patients with diabetes mellitus. On the basis of the pertinent available literature and clinical experience, we propose a quantitative definition of the dawn phenomenon, discuss potential pathogenic mechanisms, and suggest management options. The "dawn phenomenon" is a term used to describe hyperglycemia or an increase in the amount of insulin needed to maintain normoglycemia, occurring in the absence of antecedent hypoglycemia or waning insulin levels, during the early morning hours. To be clinically relevant, the magnitude of the dawn increase in blood glucose level should be more than 10 mg/dL or the increase in insulin requirement should be at least 20% from the overnight nadir. Controversy exists regarding the frequency, reproducibility, and pathogenesis of the dawn phenomenon. Approximately 54% of patients with type 1 diabetes and 55% of patients with type 2 diabetes experience the dawn phenomenon when the foregoing quantitative definition is used. The most likely pathogenic mechanism underlying the dawn phenomenon is growth hormone-mediated impairment of insulin sensitivity at the liver and muscles. The exact biochemical pathways involved are unknown. Therapeutic decisions aimed at correcting fasting hyperglycemia should take into account the variability and magnitude of the dawn phenomenon within individual patients. Successful insulinization appears to minimize the effects of the dawn phenomenon. Currently, no subcutaneous depot preparation of insulin exists that is capable of mimicking the basal insulinsecretion of the healthy pancreas. Increases in the bedtime doses of hypoglycemic agents with nighttime peaks in action may correct early morning hyperglycemia but be associated with undesirable nocturnal hypoglycemia. Targeted continuous subcutaneous insulin infusion programming can facilitate the prevention of early morning hyperglycemia in selected patients.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... In 1981, Schmidt and colleagues labeled this observation, the dawn phenomenon [1,2]. Since then, the dawn phenomenon has been defined as either early morning hyperglycemia, an increase in early morning insulin requirements in order to maintain normoglycemia, or both and has been identified in both patients with varying pathophysiological causes for diabetes and is recognized as an example of glycemic variability (GV) [3][4][5][6][7][8]. The impact of GV over time can result *Corresponding Author: Michelle R DeGeeter, PharmD, CDE Wingate University School of Pharmacy, Hendersonville, NC 28739 828-697-0105 ext 602; Email: m.degeeter@wingate.edu in poor glycemic control and is a suggested factor associated with diabetic micro-and macrovascular complications, including retinopathy, neuropathy, nephropathy, and cardiovascular disease (CVD); however, controversy exists surrounding the overall frequency and clinical implications of the dawn phenomenon and GV [3,4,7,[9][10][11][12][13]. ...
... Since then, the dawn phenomenon has been defined as either early morning hyperglycemia, an increase in early morning insulin requirements in order to maintain normoglycemia, or both and has been identified in both patients with varying pathophysiological causes for diabetes and is recognized as an example of glycemic variability (GV) [3][4][5][6][7][8]. The impact of GV over time can result *Corresponding Author: Michelle R DeGeeter, PharmD, CDE Wingate University School of Pharmacy, Hendersonville, NC 28739 828-697-0105 ext 602; Email: m.degeeter@wingate.edu in poor glycemic control and is a suggested factor associated with diabetic micro-and macrovascular complications, including retinopathy, neuropathy, nephropathy, and cardiovascular disease (CVD); however, controversy exists surrounding the overall frequency and clinical implications of the dawn phenomenon and GV [3,4,7,[9][10][11][12][13]. Currently, guidelines from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) provide little direction for providers in terms of whether treatment is required for this dysglycemia and what treatment is most effective [14,15]. ...
... Individuals without diabetes have a circadian change in insulin secretion and plasma level, which rises in the early morning, peaks midday, and declines in the evening [16]. Therefore, a true dawn phenomenon is not seen in these individuals as the increase in insulin released adequately suppresses the increase in early morning blood glucose levels [4,6,9,17,18]. ...
Article
A 42 years old woman was presented at a private clinic with right renal colic and a history of liver hydatid cyst, abdominal examination revealed mild hepatomegaly, abdominal tenderness and palpable right kidney. The radiological findings demonstrated an enlarged liver and increased parenchyma echo-texture, well defined multiples cyst were seen at both lobes with different, size, thin wall regular outline, the largest one measuring 28.3 x 25.6 mm , with bilateral multiple renal cysts and was finally diagnosed as ADPKD with liver cyst as an extra-renal manifestation of ADPKD. This extra-renal manifestation of ADPKD as liver cyst may be misdiagnosed as liver hydatid cyst.
... In the overall T2D population, the 24-h mean glucose levels and glycated hemoglobin (HbA1c) levels in patients with DP are over 12 mg/dl and 0.4% (4 mM), respectively, higher than patients without DP, which is not mitigated by dietary interventions [13,16]. The current treatment for DP is limited to symptom management; for example, by long-acting insulin analogs administered before bedtime or by continuous subcutaneous insulin infusion (CSII) with special nocturnal programming [17]. In T2D, a combination of insulin secretagogues and insulin sensitizers can ameliorate DP. ...
... Depletion of REV-ERBα/β in GABA neurons in the mouse brain (REV-GABA-KO) causes glucose intolerance and hepatic insulin resistance only at waking and not during sleep, which resembles the extended DP. These results suggest that DP is likely to be due to the altered central circadian clock in the brain, which leads to failure to Box 1. Prevalence of the DP The reported prevalence of DP ranged from 20% to 90% in T1D and 6% to 90% in T2D [17]. Earlier studies on DP are dependent on fingertip glucose measurements every few hours, which might miss the DP time points that caused the variations of the DP prevalence mentioned earlier. ...
... GH decreases glucose utilization and increases lipolysis. The rise of GH during early sleep may contribute to the trough of glucose tolerance in the middle of sleep in normal subjects, while an abnormal rise of GH before waking may contribute to DP [17,109]. Some studies found that bedtime administration of SST or SST analogs in type 1 diabetes (T1D) patients alleviates nocturnal or early-morning hyperglycemia [110][111][112], but other studies did not observe beneficial effects and advised against the use of SST analogs due to side effects [113,114]. ...
Article
Full-text available
The circadian clock provides cue-independent anticipatory signals for diurnal rhythms of baseline glucose levels and glucose tolerance. The central circadian clock is located in the hypothalamic suprachiasmatic nucleus (SCN), which comprises primarily GABAergic neurons. The SCN clock regulates physiological diurnal rhythms of endogenous glucose production (EGP) and hepatic insulin sensitivity through neurohumoral mechanisms. Disruption of the molecular circadian clock is associated with the extended dawn phenomenon (DP) in type 2 diabetes (T2D), referring to hyperglycemia in the early morning without nocturnal hypoglycemia. The DP affects nearly half of patients with diabetes, with poorly defined etiology and a lack of targeted therapy. Here we review neural and secreted factors in physiological diurnal rhythms of glucose metabolism and their pathological implications for the DP.
... Термин ФУЗ был впервые предложен в 1981 г. для описания утренней гипергликемии натощак [11]. Позднее определение было уточнено: «гипергликемия или повышенная потребность в инсулине для поддержания нормогликемии в утренние часы, развившиеся без предшествующей гипогликемии или передозировки инсулина» [12]. ФУЗ наиболее выражен у подростков, а аналогичный феномен, наблюдаемый в вечернее время у детей младшего возраста, получил название «реверсивного» ФУЗ, или ФВЗ [5]. ...
... Для ФУЗ у подростков характерна высокая потребность в инсулине во второй половине ночи и в ранние утренние часы [4,5,13]. У взрослых также выявляется ФУЗ, но менее выраженный по сравнению с подростками [12,17,18]. После того как в качестве критериев ФУЗ у взрослых были предложены «повышение гликемии более чем на 10 мг/дл или увеличение дозы инсулина более чем на 20%», данный феномен был выявлен у 54% взрослых пациентов с СД1 [12]. ...
... У взрослых также выявляется ФУЗ, но менее выраженный по сравнению с подростками [12,17,18]. После того как в качестве критериев ФУЗ у взрослых были предложены «повышение гликемии более чем на 10 мг/дл или увеличение дозы инсулина более чем на 20%», данный феномен был выявлен у 54% взрослых пациентов с СД1 [12]. ...
Article
Backgraund: Children with type 1 diabetes mellitus (T1DM) need more insulin late in the evening (reverse dawn phenomenon (RDP)), and adolescents need more insulin yearly in the morning (dawn phenomenon (DP)); these cause blood glucose variability. Modern long acting insulin analogues allow to achieve satisfactory glycemic control. Aims: To study the characteristics of insulin therapy in children and adolescents with T1DM using insulin analogues detemir and degludec to overcome blood glucose variability caused by DP and RDP in different age periods. Materials and methods: We analyzed medical documents of 200 patients using detemir, admitted to pediatric endocrinology department in 2013–2019, at mean age 9.0 years (5.4; 13.0), with T1DM for 1.3 years (0.5; 3.0); and medical documents of 50 patients switched to degludec in 2018–2019 at mean age 12.0 years (10.5; 14.5) with T1DM for 3.0 years (1.5; 6.0). Before degludec they were on intensive insulin therapy with glargine (22), detemir (26), or insulin pump (2); 16 patients (32%) presented with clinical characteristics of DP, and 5 (10%) — RDP. Results: 67 children of 108 (62%) aged 1–9 years had redistribution of detemir doses to daytime; 58 adolescents of 92 (63%) aged 10–17 лет — to nighttime. Patients switched to degludec demonstrated decrease in HbA1с from 8.7% (7.8; 9.9) to 8.0% (7.4; 9.0) (р<0.001); fasting blood glucose from 9.8 mmol/l (7.4; 11.7) to 7.7 mmol/l (6.4; 8.6) (р<0.001); within-day variability from 35.2% (31.6; 40.9) to 23.5% (19.7; 28.6) (р<0.001); daily insulin dose from 0.98 U/kg/day (0.82; 1.14) to 0.87 U/kg/day (0.75; 1.07) (р=0.002). Sub-groups of patients with DP and RDP demonstrated decrease in fasting blood glucose (from 11.5 mmol/l (9.8; 13.8) to 7.5 mmol/l (6.6; 9.1) (р<0.001)), and late evening blood glucose (from 11.0 mmol/l (10.2; 11.2) to 8.0 mmol/l (6.7; 9.5) (р= 0.03)) correspondently. Achieved levels of glycemic control did not differ between sub-groups of patients initially using glargine or detemir. Conclusions: Compensation of T1DM may be complicated due to DP and RDP. Switching to degludec allowed to achieve better glycemic control and lowering of blood glucose variability caused by DP and DRP.
... The glucose intolerance observed in knockout mice at waking resembles the 'dawn phenomenon'-an increase in the levels of blood glucose in the early morning, which affects about 50% of patients with diabetes 13 . The dawn phenomenon has mostly been studied in type 1 diabetes, and was attributed to waning levels of exogenous insulin at night in patients with type 1 diabetes 13,14 . ...
... The glucose intolerance observed in knockout mice at waking resembles the 'dawn phenomenon'-an increase in the levels of blood glucose in the early morning, which affects about 50% of patients with diabetes 13 . The dawn phenomenon has mostly been studied in type 1 diabetes, and was attributed to waning levels of exogenous insulin at night in patients with type 1 diabetes 13,14 . The altered sensitivity to insulin in our mouse model suggests that disruption of the circadian clock might be particularly related to the dawn phenomenon in type 2 diabetes. ...
Article
Full-text available
Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking1,2. The molecular mechanism that underlies this temporal pattern is unclear. Here we show that the nuclear receptors REV-ERB-α and REV-ERB-β (referred to here as ‘REV-ERB’) in the GABAergic (γ-aminobutyric acid-producing) neurons in the suprachiasmatic nucleus (SCN) (SCNGABA neurons) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviours during regular light–dark cycles. REV-ERB regulates the rhythmic expression of genes that are involved in neurotransmission in the SCN, and modulates the oscillatory firing activity of SCNGABA neurons. Chemogenetic stimulation of SCNGABA neurons at waking leads to glucose intolerance, whereas restoration of the temporal pattern of either SCNGABA neuron firing or REV-ERB expression rescues the time-dependent glucose metabolic phenotype caused by REV-ERB depletion. In individuals with diabetes, an increased level of blood glucose after waking is a defining feature of the ‘extended dawn phenomenon’3,4. Patients with type 2 diabetes with the extended dawn phenomenon exhibit a differential temporal pattern of expression of REV-ERB genes compared to patients with type 2 diabetes who do not have the extended dawn phenomenon. These findings provide mechanistic insights into how the central circadian clock regulates the diurnal rhythm of hepatic insulin sensitivity, with implications for our understanding of the extended dawn phenomenon in type 2 diabetes.
... Later, the dawn phenomenon or dawn effect was considered to be an abnormal increase in blood glucose that occurs usually between 02:00 and 08:00 in people with diabetes and between 04:00 and 08:00 in people without diabetes (3). In present, there are three definitions of dawn phenomenon: 1) an absolute dawn increase in glucose level above 10 mg/dl or the increase in insulin requirement should be at least 20% from the overnight nadir; 2) an absolute dawn increase in glucose level above 20 mg/dl and 3) a relative increase of glucose level during night with more than 6.9% (4)(5)(6). ...
... Similar with other data previously reported for type 2 diabetes patients, almost two-thirds (64.12%) of our patients presented dawn phenomenon (4,23). The frequency of dawn phenomenon was higher in younger patients. ...
Article
Full-text available
Introduction. Dawn phenomenon could have deleterious effect on overall glycemic control. Glycemic variability may be an independent risk factor for the development of diabetes chronic complications. The study aimed to evaluate any correlations between the dawn phenomenon and parameters of glycemic variability in a cohort of type 2 diabetes patients (T2DM). Material and methods. This retrospective observational study included 131 T2DM patients. Continuous glucose monitoring (CGM) has been performed. Data from the first 24h of full recording were used for analysis of glycemic variability indices: mean level of 24h interstitial glucose value and standard deviation; % coefficient of variation; J index; mean amplitude of glycemic excursion - MAGE; continuous overall net glycemic action (CONGA) at 1, 2, 4 and 6 hours; mean of daily differences (MODD) index. Results. Mean age was 56.04 ± 9.91 years, 35.9% women, 17.6% on diet, 53.4% on oral therapy and 29% on insulin. Dawn phenomenon was more frequent in patients below 60 years (70%) and in oral therapy group (72.85%). Significant correlations between the dawn phenomenon and j-index, MAGE, CONGA-4 and CONGA-6 have been found in T2DM patients on diet therapy alone. The amplitude of dawn phenomenon was 46.10 ± 24.40 mg/dl and significantly correlated (p<0.05) after adjustment for age, gender and treatment with % CV, MAGE, CONGA-1, CONGA-2, CONGA-4, CONGA-6 and MODD. Conclusions. The dawn phenomenon significantly increases the glycemic variability parameters in drug-naive T2DM patients, with no impact in T2DM on oral or insulin therapy. © 2016 University of Medicine and Pharmacy Targu Mures. All rights reserved.
... Therefore it is encouraging that the improvements overnight were sustained after discontinuation, especially as maintaining glycaemic control during the morning period can be challenging with over 50% of patients with type 1 diabetes experiencing higher glucose levels. [142] In my study, during conventional CSII visits subjects spent 75% of time in hyperglycaemia after breakfast. This is known as the dawn phenomenon, and may be associated with growth hormone-induced impairment in insulin sensitivity in liver and muscle. ...
... Insulin requirements are generally higher in the morning, associated with the dawn phenomenon. [142] Interestingly, three participants chose to set a 20 − 30% reduction in their usual CSII rates for up to ten hours following consumption of the wine as per their usual practice. My study suggests that such reduction may not be necessary, and in fact may contribute to elevated glucose levels the following morning. ...
Thesis
Achieving tight glucose control safely in type 1 diabetes with currently available methods of insulin delivery is challenging. Aggressive regimens carry an increased risk of hypoglycaemia, particularly overnight. Both alcohol consumption and exercise predispose further to low glucose levels. The demands are even greater in pregnancy where, in addition to limiting hypoglycaemia, avoidance of postprandial hyperglycaemia is critical to minimising adverse obstetric outcomes. The aim of my studies was to evaluate feasibility and safety of a closed-loop or ’artificial pancreas’ system linking insulin delivery with continuous glucose monitoring (CGM), in adults with type 1 diabetes in a controlled setting. Three randomised crossover studies compared closed-loop insulin delivery with conventional insulin pump therapy on two separate occasions, matched in meals and activities. During closed-loop visits, CGM values were entered into a computer containing a model predictive control algorithm which advised on basal insulin infusion for subcutaneous delivery, every 15 minutes. During control visits, usual insulin pump regimen was continued. The feasibility study evaluated overnight closed-loop in 12 adults (seven females, mean age 37.7 years, HbA1c 7.8%) following 60g- carbohydrate evening meal. A follow-up study assessed overnight closed-loop in 12 further adults (seven females, mean age 37.2 years, HbA1c 7.8%) following 100g-carbohydrate meal and (mean 564 ml) white wine. The third study evaluated 24 hours of closed-loop in 12 pregnant women (mean age 32.9 years, 19 to 23 weeks gestation, HbA1c 6.4%) during normal daily activities, including low and moderate intensity exercise. Activity and glucose levels were also measured during free-living. CGM performance during exercise was evaluated. Overnight closed-loop insulin delivery in adults, compared with conventional pump therapy, increased time spent with plasma glucose in target range (3.9−8.0 mmol/l) following both standard meal (81% versus 57%; p = 0.012) and large meal accompanied by alcohol (70% versus 46%; p = 0.012). Glycaemic variability, and time spent in hypo- and hyper- glycaemia were lowered. In pregnant women, day and night closed-loop insulin delivery was as effective as usual pump regimen (81% versus 81% time spent with plasma glucose 3.5−7.8 mmol/l; p = 0.754). Hypoglycaemia occurred following exercise, although closed-loop prevented nocturnal episodes. Glycaemic control during free-living was suboptimal, compared with controlled diet and exercise conditions. Accuracy of CGM was lower during exercise. In conclusion, these studies confirm the feasibility and efficacy of overnight closed-loop insulin delivery in adults with type 1 diabetes. Closed-loop is safe during pregnancy and may be beneficial in women with suboptimal glycaemic control. Meals and physical activity currently limit optimal daytime use of closed-loop.
... By definition, it is the rise in blood glucose concentration in the early morning hours when not preceded by hypoglycemia or insulin deficiency. This terminology was first used by Schmidt et al. (2) and subsequently later defined by numerous other authors according to several parameters including: 1) the specific period of time in the morning, 2) the magnitude of the glucose elevation, and 3) whether it is the rise in glucose or the need for more insulin to maintain euglycemia (3,4). All authors agree, however, that it is a principal cause of early morning hyperglycemia and poor glucose control, particularly in type 1 diabetes (5)(6)(7). ...
... Both physiological and sensor obtained parameters were correlated to the occurrence of the Dawn Phenomenon. The Dawn Phenomenon was defined as an early morning increase in glucose (between the overnight nadir and the breakfast meal) of 10mg/dl or greater not preceded by hypoglycemia, as previously described (4). Subjects wore the CGM for a maximum of 5 days per study period, permitting analysis of a maximum of 4 overnight recordings. ...
... Therefore it is encouraging that the improvements overnight were sustained after discontinuation, especially as maintaining glycaemic control during the morning period can be challenging with over 50% of patients with type 1 diabetes experiencing higher glucose levels. [142] In my study, during conventional CSII visits subjects spent 75% of time in hyperglycaemia after breakfast. This is known as the dawn phenomenon, and may be associated with growth hormone-induced impairment in insulin sensitivity in liver and muscle. ...
... Insulin requirements are generally higher in the morning, associated with the dawn phenomenon. [142] Interestingly, three participants chose to set a 20 − 30% reduction in their usual CSII rates for up to ten hours following consumption of the wine as per their usual practice. My study suggests that such reduction may not be necessary, and in fact may contribute to elevated glucose levels the following morning. ...
Article
Full-text available
Achieving tight glucose control safely in type 1 diabetes with currently available methods of insulin delivery is challenging. Aggressive regimens carry an increased risk of hypoglycaemia, particularly overnight. Both alcohol consumption and exercise predispose further to low glucose levels. The demands are even greater in pregnancy where, in addition to limiting hypoglycaemia, avoidance of postprandial hyperglycaemia is critical to minimising adverse obstetric outcomes. The aim of my studies was to evaluate feasibility and safety of a closed-loop or ’artificial pancreas’ system linking insulin delivery with continuous glucose monitoring (CGM), in adults with type 1 diabetes in a controlled setting. Three randomised crossover studies compared closed-loop insulin delivery with conventional insulin pump therapy on two separate occasions, matched in meals and activities. During closed-loop visits, CGM values were entered into a computer containing a model predictive control algorithm which advised on basal insulin infusion for subcutaneous delivery, every 15 minutes. During control visits, usual insulin pump regimen was continued. The feasibility study evaluated overnight closed-loop in 12 adults (seven females, mean age 37.7 years, HbA1c 7.8%) following 60g- carbohydrate evening meal. A follow-up study assessed overnight closed-loop in 12 further adults (seven females, mean age 37.2 years, HbA1c 7.8%) following 100g-carbohydrate meal and (mean 564 ml) white wine. The third study evaluated 24 hours of closed-loop in 12 pregnant women (mean age 32.9 years, 19 to 23 weeks gestation, HbA1c 6.4%) during normal daily activities, including low and moderate intensity exercise. Activity and glucose levels were also measured during free-living. CGM performance during exercise was evaluated. Overnight closed-loop insulin delivery in adults, compared with conventional pump therapy, increased time spent with plasma glucose in target range (3.9−8.0 mmol/l) following both standard meal (81% versus 57%; p = 0.012) and large meal accompanied by alcohol (70% versus 46%; p = 0.012). Glycaemic variability, and time spent in hypo- and hyper- glycaemia were lowered. In pregnant women, day and night closed-loop insulin delivery was as effective as usual pump regimen (81% versus 81% time spent with plasma glucose 3.5−7.8 mmol/l; p = 0.754). Hypoglycaemia occurred following exercise, although closed-loop prevented nocturnal episodes. Glycaemic control during free-living was suboptimal, compared with controlled diet and exercise conditions. Accuracy of CGM was lower during exercise. In conclusion, these studies confirm the feasibility and efficacy of overnight closed-loop insulin delivery in adults with type 1 diabetes. Closed-loop is safe during pregnancy and may be beneficial in women with suboptimal glycaemic control. Meals and physical activity currently limit optimal daytime use of closed-loop.
... To assess daily glucose level fluctuations, each subject's glucose level was monitored continuously from Day 1 to Day 6 using a CGM device (iPro2 Professional CGM; Medtronic, Northridge, PA, USA). The dawn phenomenon (Δdawn, mg/dL), stochastic spontaneous glucose fluctuations during the early morning period after an overnight fast, was quantified by subtracting the nocturnal glucose nadir from the glucose value observed just before breakfast [23]; the dawn phenomenon was considered to be present if the glucose level increased by ≥20 mg/dL, as previously reported [23,24]. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR), which has been widely used in large population studies [25,26]. ...
... To assess daily glucose level fluctuations, each subject's glucose level was monitored continuously from Day 1 to Day 6 using a CGM device (iPro2 Professional CGM; Medtronic, Northridge, PA, USA). The dawn phenomenon (Δdawn, mg/dL), stochastic spontaneous glucose fluctuations during the early morning period after an overnight fast, was quantified by subtracting the nocturnal glucose nadir from the glucose value observed just before breakfast [23]; the dawn phenomenon was considered to be present if the glucose level increased by ≥20 mg/dL, as previously reported [23,24]. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR), which has been widely used in large population studies [25,26]. ...
Article
Full-text available
Introduction Acute and chronic insomnia can exacerbate type 2 diabetes mellitus (T2DM). We investigated suvorexant (an anti-insomnia drug that targets the orexin system) effects on sleep architecture and glucose metabolism in T2DM patients with insomnia. Materials and methods This 7 day open-label, single-arm, intervention trial included 18 subjects with T2DM and insomnia. After 1 day acclimatization, daily glucose levels, sleep architecture, and autonomic nervous function were evaluated by continuous glucose monitoring (CGM), single-channel electroencephalography, and accelerometry, respectively. Results Suvorexant treatment for 3 days significantly increased total sleep time and sleep efficiency, with partial suppression of sympathetic nerve activity. CGM-measured 24 h mean glucose level decreased significantly from 157.7 ± 22.9 to 152.3 ± 17.8 mg/dL, especially in the early glucose surge after the midnight nadir (from 28.3 ± 15.0 to 18.2 ± 9.9 mg/dL), and until supper with a significant improvement in homeostasis model assessment of insulin resistance from 4.0 ± 2.8 to 2.9 ± 1.6, respectively. Conclusions Suvorexant treatment for insomnia of subjects with T2DM significantly improved CGM-measured daily glycemic control, which was associated with changes in sympathomimetic tone and/or improved insulin sensitivity. The amelioration of insomnia may therefore be a target for improving glycemic control in T2DM patients with insomnia.
... The dawn phenomenon frequently results in unacceptable early morning hyperglycemia in type 1 diabetes; however, the optimal management of this problem remains controversial (1). Continuous subcutaneous insulin infusion (CSII) allows for variable nocturnal infusion rates and has been shown in short-term inpatient studies to reduce the occurrence of the dawn phenomenon (2,3). ...
... To investigate the effects of programming an early morning increase in insulin delivery on the occurrence of the dawn phenomenon and hypoglycemia, we compared the CSII programmers to nonprogrammers. The dawn phenomenon was defined as an early morning increase in CGM-determined glucose between the overnight nadir (occurring between 2:00 and 5:00 am) and the breakfast meal (occurring between 5:00 and 10:00 am) of 10 mg/dL, as previously reported (1,5,7,15). Early morning increases in glucose of greater than 10 mg/dL preceded by hypoglycemia were excluded from analysis to avoid introducing the confounding effect of counterregulatory responses to hypoglycemia in our data interpretation. ...
Article
Objective: Continuous subcutaneous insulin infusion (CSII) programming for an early morning increase in insulin delivery is frequently recommended to counteract the rise in glucose prior to breakfast (dawn phenomenon). However, both the effectiveness and safety of this approach have not been tested in the ambulatory setting. Using continuous glucose monitoring, we investigated the safety and effectiveness of early morning CSII programming for management of the dawn phenomenon in subjects with type 1 diabetes.Methods: We conducted a controlled, observational eight-month longitudinal study of type 1 diabetic patients (n=40). Reproducibility of the dawn phenomenon was determined in subjects treated with multiple daily injections of insulin (MDI, n=12) and those on CSII who did not program an early morning increase in insulin delivery (CSII non-programmers, n=8). The effects of early morning CSII programming were determined by comparing rates of the dawn phenomenon and hypoglycemia in CSII non-programmers versus CSII-users who programmed an early morning increase in insulin delivery (CSII programmers, n=20).Results: The dawn phenomenon occurred in all tested subjects to a variable extent (median rate 56% of nights). CSII programming was not associated with a reduction in the occurrence of the dawn phenomenon (42%) compared to non-programmers (48%) (P=0.47) nor in the magnitude of the dawn phenomenon. Hypoglycemia occurred more frequently in the CSII programmers (37%) compared to non-programmers (18%) (P=0.001).Conclusion: The dawn phenomenon occurs unpredictably; therefore, early morning CSII programming for a fixed increase in early morning insulin delivery is ineffective and may be hazardous to the patient.
... Currently, healthcare providers fail to take the dawn phenomenon into consideration as one of the targets in the management of the disorder. This is very likely linked to the fact that its quantification requires CGM to accurately detect the nocturnal glucose nadir [4][5][6][7], and permit the calculation of the absolute differences between the nocturnal glucose nadir and pre-breakfast glucose values [3,4]. Access to CGM remains costly and is therefore only available to physicians working at clinics located in specialized diabetes units [8]. ...
Article
Aim: The study was aimed at determining whether the dawn phenomenon in type 2 diabetes (T2D) can be predicted and quantified using simple and easily accessible glucose determinations. Methods: A total of 210 non-insulin-treated persons with T2D underwent continuous glucose monitoring (CGM). The dawn phenomenon was quantified as the absolute increment from the nocturnal glucose nadir to the pre-breakfast value (Δdawn, mg/dL). Pre-lunch (preL) and pre-dinner (preD) glucose, and their averaged values (preLD), were compared with the nocturnal nadir. These pre-meal values were subtracted from the pre-breakfast values. The differences obtained (Δpre-mealL, Δpre-meal D and Δpre-meal LD) were correlated with Δdawn values. The receiver operating characteristic (ROC) curve was used to select the optimal Δpre-meal value that best predicted a dawn phenomenon, set at a threshold of 20mg/dL. Results: All pre-meal glucose levels and differences from pre-breakfast values (Δpre-meal) significantly correlated (P<0.0001) with the nocturnal nadir and Δdawn values, respectively. The strongest correlations were observed for the parameters averaged at preL and preD time points: r=0.83 for preLD and r=0.58 for Δpre-meal LD. ROC curve analysis indicated that the dawn phenomenon at a threshold of 20mg/dL can be significantly predicted by a Δpre-meal LD cut off value of 10mg/dL. The relationship between Δdawn (Y, mg/dL) and Δpre-meal LD (X, mg/dL) was Y=0.49 X+15. Conclusion: The self-monitoring of preprandial glucose values at the three main mealtimes can predict the presence/absence of the dawn phenomenon, and permits reliable assessment of its magnitude without requiring continuous overnight glucose monitoring.
... Achieving adequate fasting blood glucose control prior to breakfast, also known as the dawn phenomenon [36], was identified as a challenge for most women in this survey, regardless of whether their recommended glycaemic targets [39] but require further research for women with GDM. Two-thirds of women commented on being hungry. ...
Article
Full-text available
Introduction Optimal glycaemic control in women with gestational diabetes mellitus (GDM) reduces maternal and infant morbidity. Method A survey was administered to women diagnosed with GDM to explore their views and experiences in achieving optimal glycaemic control. Results Sixty women participated. Enablers included being taught to test capillary blood glucose in group settings where the health professional demonstrated this on themselves first (60, 100%); health professionals listening (41, 68%); being reminded to perform blood glucose testing (33, 55%); and being provided healthy meals by friends and family (28, 47%). Barriers included not having information in a woman's first language (33, 55%); being offered unhealthy food (19, 31%); not being believed by health professionals (13, 21%); receiving inconsistent information by health professionals (10, 16%); never being seen twice by the same health professional (8, 13%); and long waiting hours at clinics (7, 11%). Two-thirds of women (37, 62%) reported that food costs were not a barrier, but that they were always or frequently hungry. Conclusion Optimising experiences for women with GDM for achieving glycaemic control and overcoming barriers, regardless of glycaemic targets, requires further focus on providing meaningful health literacy and support from health professionals, family, friends, and work colleagues.
... Despite these difficulties, postprandial glucose control was found to be acceptable in the present study while there were no restrictions in diet, which anecdotally led to patients to challenge the artificial pancreas with, for example, exceptionally large meals. Glucose control after breakfast seemed to be most challenging, which may be partly explained by lower insulin sensitivity in the morning and already increasing blood glucose (dawn phenomenon) before breakfast [16]. The integration of the different components in one device avoids connectivity problems between the CGM, control algorithm and infusion pumps. ...
Article
Full-text available
Aims: To assess the performance and safety of an integrated bihormonal artificial pancreas system consisting of one wearable device and two wireless glucose sensor transmitters during short-term daily use at home. Methods: Adult patients with type 1 diabetes using an insulin pump were invited to this randomized cross-over study. Treatment with the artificial pancreas started with one day and night in the clinical research center, followed by three days at home. The control period consisted of four days of insulin pump therapy at home with blinded continuous glucose monitoring for data collection. Day two until four were predefined as the analysis period with median glucose as the primary outcome. Results: Ten patients completed the study. The median (IQR) glucose level was comparable for the two treatments (7.3 [7.0-7.6] mmol/l for the artificial pancreas vs. 7.7 [7.0-9.0] mmol/l for the control, p = 0.123). Percentage of time spent in euglycemia (3.9-10 mmol/l) was increased during use of the artificial pancreas (84.7 [82.2-87.8]% vs. 68.5 [57.9-83.6]% for the control, p = 0.007). Time in hypoglycemia was 1.3 (0.2-3.2)% for the artificial pancreas and 2.4 (0.4-10.3)% for the control treatment (p = 0.139). Separate analysis of daytime and nighttime showed that the improvements were mainly achieved during the night. Conclusions: The results of this pilot study suggest that our integrated artificial pancreas provides better glucose control than insulin pump therapy in patients with type 1 diabetes at home and that the treatment is safe.
... Intrasubject variability can be influenced by acute illness, stress, alcohol, 41 physical activity and variations in counter-regulatory hormone levels during the day. 42 To perform optimally, closed-loop systems will have to be able to adapt and compensate for these variations. ...
Article
Tight glycaemic control in type 1 diabetes mellitus has been shown to be important for the prevention of long-term microvascular complications. Consequently, intensive insulin treatment has been advocated in the attempt to achieve normal glycaemia. This has proven challenging mainly due to an increased risk of hypoglycaemia associated with the intensive insulin regimen. Closed-loop systems for glucose control, designed to mimic the endocrine action of the healthy pancreas without human intervention, may provide a solution. The vital component of a closed-loop system, often referred to as an artificial pancreas, is a computer-based algorithm. Other components include a real-time continuous glucose monitor and an infusion pump to titrate and deliver insulin. The role of the control algorithm is to translate, in real-time, the information it receives from the glucose monitor and to compute the amount of insulin to be delivered by the pump. This review article describes the individual components of the artificial pancreas, and aims to highlight existing clinical evidence from studies performed on available artificial pancreas prototypes. Current limitations and obstacles facing this technology are reviewed, together with its potential direction in the future. By achieving normal glycaemia and reducing the risk of hypoglycaemia, the artificial pancreas could potentially improve the lives of patients with type 1 diabetes and act as a ‘bridge’ until a cure for type 1 diabetes is found. © 2012 FEND. Published by John Wiley & Sons, Ltd.
... In certain cases, changes in target tissue sensitivity can play a dominant role. This increases, decreased hepatic insulin sensitivity driving gluconeogenesis prior to waking (resulting in the Dawn Phenomenon) Carroll & Schade, 2005;Schmidt et al., 1984), as well as TODdependent oscillations in renal ACTH sensitivity, which drives oscillations in cortisol secretion (Dickmeis, 2009). ...
Article
Full-text available
Triiodothyronine (T3) is an important modulator of cardiac metabolism and function, often through modulation of gene expression. The cardiomyocyte circadian clock is a transcriptionally based molecular mechanism capable of regulating cardiac processes, in part by modulating responsiveness of the heart to extra-cardiac stimuli/stresses in a time-of-day (TOD)-dependent manner. Although TOD-dependent oscillations in circulating levels of T3 (and its intermediates) have been established, oscillations in T3 sensitivity in the heart is unknown. To investigate the latter possibility, euthyroid male Wistar rats were treated with vehicle or T3 at distinct times of the day, after which induction of known T3 target genes were assessed in the heart (4-h later). The expression of mRNA was assessed by real-time quantitative polymerase chain reaction (qPCR). Here, we report greater T3 induction of transcript levels at the end of the dark phase. Surprisingly, use of cardiomyocyte-specific clock mutant (CCM) mice revealed that TOD-dependent oscillations in T3 sensitivity were independent of this cell autonomous mechanism. Investigation of genes encoding for proteins that affect T3 sensitivity revealed that Dio1, Dio2 and Thrb1 exhibited TOD-dependent variations in the heart, while Thra1 and Thra2 did not. Of these, Dio1 and Thrb1 were increased in the heart at the end of the dark phase. Interestingly, we observed that T3 acutely altered the expression of core clock components (e.g. Bmal1) in the rat heart. To investigate this further, rats were injected with a single dose of T3, after which expression of clock genes was interrogated at 3-h intervals over the subsequent 24-h period. These studies revealed robust effects of T3 on oscillations of both core clock components and clock-controlled genes. In summary, the current study exposed TOD-dependent sensitivity to T3 in the heart and its effects in the circadian clock genes expression.
... Although the dawn phenomenon is not caused by insulin deficiency, effective insulin delivery can minimize its hyperglycemic effects. Strategies to prevent the dawn phenomenon should be tailored to the individual patient and should balance the risks of undesirable overnight hypoglycemia against optimal correction of fasting hyperglycemia [68]. ...
Article
This review addresses the effects of growth hormone on diurnal insulin sensitivity in normal, patients with type 2 diabetes mellitus (T2DM) and animal models described in our previous studies. Results confirmed the presence of diurnal insulin sensitivity, or greater insulin sensitivity in the morning, in normal subjects. The exact cause of this circadian rhythm in plasma glucose levels in healthy subjects has not been established, and nocturnal surges in growth hormone secretion remain a possible explanation. Results showed that growth hormone is an important factor controlling the diurnal variation of glucose tolerance and insulin sensitivity in rats. Data from our previous study provided direct evidence that the role of growth hormone in regulating insulin sensitivity in healthy subjects may be related to changes in the metabolic clearance rate of insulin and the metabolism of non-esterified fatty acids. A different circadian rhythm for plasma glucose appears to be present in patients with T2DM with nadirs in the early evening and peaks in the early morning, indicating greater insulin sensitivity in the evening. As in normal subjects, the exact cause of these circadian rhythms in the plasma glucose levels of patients with T2DM provided direct evidence that the reduction in insulin sensitivity may be due to the nocturnal surge of growth hormone in the early morning hours.
... A lunch test meal was chosen for two reasons. First, for the purpose of circumventing the insulin resistance variably induced by the Dawn phenomenon at breakfast [7] and second, because a diabetic patient coming from a significant distance for medical care would frequently ingest lunch before an afternoon blood draw. ...
... Еще одной важной проблемой, осложняющей проведение инсулинотерапии, является «феномен утренней зари». Считается, что частота его распространенности составляет 54% у пациентов с СД1 [31]. Пациентам с выраженной гипергликемией в ранние утренние часы может быть рекомендован переход на помповую инсулинотерапию с увеличением базальной подачи инсулина в соответствующее время [32], хотя имеются некоторые доказательства, предполагающие, что пролонгированные аналоги инсулина могут также предоставить лучший уровень метаболического контроля в ранние утренние часы по сравнению с инсулином НПХ. ...
Article
Full-text available
DCCT (Diabetes Control and Complications Trial) study established that intensified insulin therapy in multiple daily injections (MDI) or continuous insulin infusion (CSII) regimens substantially reduce both development and progression of complications in patients with type 1 diabetes mellitus (T1DM) as compared to conventional insulin therapy. Insulin analogues possess better pharmacokinetic and pharmacodynamic characteristics than unmodified human insulin agents. These characteristics are beneficial for management of diabetes mellitus, allowing better glycemic outcomes with lower incidence of hypoglycemia. Current review discusses specifics of therapy with glargine (Lantus®) and glulisine (Apidra®) insulin analogues. Authors analyzed available to date results from corresponding clinical trials in children, adolescents and adults. Pharmacoeconomic aspects and matters of dosage of glargine and glulisine are further addressed.
... growth hormones, cortisol, epinephrine and glucagon) responsible for insulin resistance, a situation also known as the 'dawn phenomenon'. 51 This phenomenon is the night-to-morning elevation in blood glucose levels before and after breakfast in subjects with both T1DM and T2DM. In people without diabetes mellitus, blood glucose and plasma insulin concentrations remain remarkably flat and constant overnight, with a modest transient increase in insulin secretion just before dawn to restrain hepatic glucose production and prevent hyperglycaemia. ...
Article
Full-text available
We discuss the bioecological model of Urie Bronfrenbreener and its application to diabetes care and psychosocial wellbeing of children with diabetes in Sub-Saharan Africa. Using empirical evidence, this paper demonstrates that the bioecological model provides an important framework for understanding diabetes care needs and intervention strategies required to enhance the well-being of children living with diabetes. The paper also discusses clinical and research implications. The advantage of applying the bioecological model in drawing up intervention strategies for those living with diabetes is that it targets large-scale public health interventions unlike medical intervention that focus on a single individual. Keywords: Bioecological Model, PPCT, Children, Adolescents, Diabetes-care, Psychosocial-wellbeing
... Le insuline basali che utilizziamo oggi sono caratterizzate da un profilo piatto con emivita intorno alle 24 ore che offre il vantaggio di avere cinetiche riproducibili e assenza di picco, cosa che si traduce in un basso rischio ipoglicemico, interprandiale e notturno (7) ; il risvolto della medaglia tuttavia è certamente il fatto che spesso l'insulinizzazione basale risulta non adeguata al risveglio e spesso nel segmento temporale pomeridiano/serale. Il rispetto del ritmo circadiano della secrezione insulinica basale è di grande importanza poiché consentirebbe di ottenere un buon profilo glicemico notturno ed evitare il picco glicemico al risveglio, il cosiddetto "fenomeno alba" che spesso condiziona il compenso glicemico nel paziente con DT1 (8) . I pattern secretori cambiano nelle diverse decadi di età ma il più elevato fabbisogno insulinico si verifica tipicamente nella prime ore del mattino (di solito dalle 4.00 alle 8.00 a.m.) ed è legato all'aumento della secrezione degli ormoni contro-regolatori (glucagone, adrenalina, cortisolo) che riducono la sensibilità insulinica (9) . ...
Article
Full-text available
The monitoring and treatment of type 1 diabetes (T1D) are undergoing profound changes today. Notable steps include the improvement and widespread adoption of glucose sensors which are now extremely reliable and furthermore are used with insulin pumps in an integrated manner. Over the last 2 to 3 years these systems have evolved rapidly with the development and use of algorithms which permit the autonomous regulation of basal insulin. Correct control and administration of basal insulin is often the greatest stumbling block in multiple daily injection therapy as basal insulins cannot replicate the physiological rhythms of basal insulin secretion. Hypoglycemia is another critical point in standard insulin pen therapy as it does not permit dosage modulation in the same way as with an insulin pump. In this article we cover the fundamental steps in this revolution of insulin therapy which promises, in the not too distant future, the ultimate achievement of the artificial pancreas and thus the complete closure of the loop. All those working in diabetes care must be adequately trained and familiar with this technology as it should no longer be considered a niche treatment reserved for carefully selected patients and managed in only a few centers of excellence. In order to choose the best treatment, tailored to each individual patient’s needs, medical staff involved in the treatment of T1D require a thorough knowledge of standalone glucose sensors, insulin pumps and integrated systems with control algorithms.Once the critical issues (costs, psychological aspects, system management difficulties, alarm fatigue, etc.) still related to their use have been resolved, new Hybrid Closed Loop and Advanced Hybrid Closed Loop systems could become the new standard in the treatment of T1D. KEY WORDS type 1 Diabetes; insulin pump; decision-making algorithms; integrated system.
... More specific issues include the dawn phenomenon (6). This is particularly difficult for the traveling patient for both multiple injections or pump(7) since the timing of the morning insulin resistance cannot be known, at least at first. ...
... Mean MARD varied by pump and basal rate: 2 units/hr-11.8% MiniMed, 10 Peak insulin delivery is achieved by frequency modulation for Omnipod, volume modulation for Tandem, and a combination for Ypsomed and Medtronic. At low basal rates delivery was better maintained if the interstroke time was held constant (with volume modulation). ...
... In some individuals, the duration of action of the longer-acting component of the predinner dose may not last until the next morning, allowing BG levels to rise unchecked secondary to the "dawn phenomenon." 63 This phenomenon is not commonly reported in clinical studies but could occur in real life. This problem could be addressed by using separate doses of short-and long-acting insulins at dinner and bedtime, respectively. ...
Article
Full-text available
... It is an autoimmune disease characterized by the loss of insulin-producing β cells of the pancreas, leading to an inability to use glucose as fuel, thus requiring life-saving exogenous insulin administration [3]. The management of glucose is challenging because patients must consider a myriad of factors when making diabetes care decisions (eg, insulin administration and glucose checks), such as the amount of carbohydrates consumed, insulin administered, physical activity, stress, illness, hormonal changes that cause natural spikes in glucose (eg, dawn phenomenon), and access to diabetes treatment technologies (eg, continuous glucose monitoring [CGM] and insulin pump) [4][5][6]. This complex web of factors and subsequent management decisions can lead to a significant amount of glucose variability throughout the day, with frequent fluctuations between normal (euglycemia), high (hyperglycemia), and low (hypoglycemia) glucose levels [4]. ...
Article
Type 1 diabetes (T1D) is one of the most common chronic childhood diseases, and its prevalence is rapidly increasing. The management of glucose in T1D is challenging, as youth must consider a myriad of factors when making diabetes care decisions. This task often leads to significant hyperglycemia, hypoglycemia, and glucose variability throughout the day, which have been associated with short- and long-term medical complications. At present, most of what is known about each of these complications and the health behaviors that may lead to them have been uncovered in the clinical setting or in laboratory-based research. However, the tools often used in these settings are limited in their ability to capture the dynamic behaviors, feelings, and physiological changes associated with T1D that fluctuate from moment to moment throughout the day. A better understanding of T1D in daily life could potentially aid in the development of interventions to improve diabetes care and mitigate the negative medical consequences associated with it. Therefore, there is a need to measure repeated, real-time, and real-world features of this disease in youth. This approach is known as ecological momentary assessment (EMA), and it has considerable advantages to in-lab research. Thus, this viewpoint aims to describe EMA tools that have been used to collect data in the daily lives of youth with T1D and discuss studies that explored the nuances of T1D in daily life using these methods. This viewpoint focuses on the following EMA methods: continuous glucose monitoring, actigraphy, ambulatory blood pressure monitoring, personal digital assistants, smartphones, and phone-based systems. The viewpoint also discusses the benefits of using EMA methods to collect important data that might not otherwise be collected in the laboratory and the limitations of each tool, future directions of the field, and possible clinical implications for their use.
... Although the three meals are similar, the peaks of glycemia and plasma insulin concentration that occur after the 2nd and 3rd meals have a much lower amplitude than those observed after the 1st meal. The larger changes observed in response to the first meal might be related to some degree of insulin resistance occurring in early morning hours, the ''dawn phenomenon" well described in diabetic patients [10] as well as in non-diabetic volunteers [11]. 2. Between meals, glycemia remains relatively stable around 5 mmol/L, the same level as that observed in the early morning, before the first meal. ...
Article
Glucagon secretion is stimulated by a low plasma glucose concentration. By activating glycogenolysis and gluconeogenesis in the liver, glucagon contributes to maintain a normal glycemia. Glucagon secretion is also stimulated by the intake of proteins, and glucagon contributes to amino acid metabolism and nitrogen excretion. Amino acids are used for gluconeogenesis and ureagenesis, two metabolic pathways that are closely associated. Intriguingly, cyclic AMP, the second messenger of glucagon action in the liver, is released into the bloodstream becoming an extracellular messenger. These effects depend not only on glucagon itself but on the actual glucagon/insulin ratio because insulin counteracts glucagon action on the liver. This review revisits the role of glucagon in nitrogen metabolism and in disposal of nitrogen wastes. This role involves coordinated actions of glucagon on the liver and kidney. Glucagon influences the transport of fluid and solutes in the distal tubule and collecting duct, and extracellular cAMP influences proximal tubule reabsorption. These combined effects increase the fractional excretion of urea, sodium, potassium and phosphates. Moreover, the simultaneous actions of glucagon and extracellular cAMP are responsible, at least in part, for the protein-induced rise in glomerular filtration rate that contributes to a more efficient excretion of protein-derived end products.
... -Additional excessive glucose exposure, which is only observed in patients with diabetes, in other words in those with HbA1c levels ≥6.5 % according to American Diabetes Association (ADA) standards [23]. This additional glucose exposure observed in persons with type 2 diabetes can be separated into three further subcomponents: (a) the dawn phenomenon [24][25][26], (b) postprandial hyperglycemia [27][28][29] and (c) basal hyperglycemia. These aforementioned dysglycemic states do not necessary occur simultaneously in the evolution of type 2 Fig. 1 Influence of duration of follow-up upon the relative risk of major cardiovascular outcomes in patients with type 2 diabetes submitted to intensive glucose-lowering as compared with standard therapy. ...
Article
Full-text available
Achieving near normal glucose homeostasis implies that all components of dysglycemia that are present in diabetes states be eliminated. Reducing ambient/overall hyperglycemia is a pre-requisite to eliminate the risk of development and progression of diabetes complications. More controversially however, are the relative and related contributions of postprandial glucose excursions, glucose variability, hypoglycemia and the dawn phenomenon across the spectrum of dysglycemia. For instance, it is likely that the dawn phenomenon contributes to ambient hyperglycemia and that postprandial glucose excursions are at the cross road of ambient hyperglycemia and glucose variability with glucose fluctuations as causative risk factors for hypoglycemia. Proof-of-concept trials such as the ongoing FLAT-SUGAR study are necessary for gaining further insight into the possible harmful effects of some of these features such as excessive glycemic variability and glucose excursions, still considered to be of minor relevance by several diabetologists. Whether their role will be more thoroughly proven through further intervention trials with “hard” endpoints, remains to be seen. In the meantime more consideration should be given to medications aimed at concomitantly reducing ambient/overall hyperglycemia and those additional abnormal glycemic features of dysglycemia.
... In certain cases, changes in target tissue sensitivity can play a dominant role. For example, a decrease in hepatic insulin sensitivity prior waking ensures gluconeogenesis (resulting in the Dawn Phenomenon) Carroll & Schade, 2005;Schmidt et al., 1984), as well as TODdependent oscillations in renal ACTH sensitivity, which drives oscillations in cortisol secretion (Dickmeis, 2009). ...
... For example, the sharp peak in NOCT expression when mice wake up (mice are nocturnal and ZT12 corresponds to awakening) must be understood from the point of NADP(H)/NAD(H) regulation. One physiological function of NOCT could be to maximize available NAD (H) for energy generation in a search for food, using elevated blood sugar that animals have at the time of awakening 26 . The demonstration that Curled cleaves NADPH reveals the molecular target of the mutant cu, which has been used for more than a century in fruit fly genetics. ...
Article
Full-text available
Nocturnin (NOCT) is a rhythmically expressed protein that regulates metabolism under the control of circadian clock. It has been proposed that NOCT deadenylates and regulates metabolic enzyme mRNAs. However, in contrast to other deadenylases, purified NOCT lacks the deadenylase activity. To identify the substrate of NOCT, we conducted a mass spectrometry screen and report that NOCT specifically and directly converts the dinucleotide NADP+ into NAD+ and NADPH into NADH. Further, we demonstrate that the Drosophila NOCT ortholog, Curled, has the same enzymatic activity. We obtained the 2.7 Å crystal structure of the human NOCT•NADPH complex, which revealed that NOCT recognizes the chemically unique ribose-phosphate backbone of the metabolite, placing the 2'-terminal phosphate productively for removal. We provide evidence for NOCT targeting to mitochondria and propose that NADP(H) regulation, which takes place at least in part in mitochondria, establishes the molecular link between circadian clock and metabolism.
... The effects of the DP and extended DP on total daily blood glucose and HbA1C were 0.67 mmol/L and 0.4%, respectively, which were not affected by the treatment regimens [2,4]. DP, one of the causes of elevated FBG, can cause an increase in blood glucose levels throughout the day, resulting in poor overall glycemic control [11,19]. The primary goal of treatment of DP is to reconstruct near-normal blood glucose values before and after breakfast to reduce daily mean blood glucose and HbA1C levels [2,4]. ...
Article
Full-text available
Background: The dawn phenomenon (DP) is the primary cause of difficulty in blood glucose management in type 2 diabetic (T2D) patients, and the use of oral hypoglycemic agents has shown weak efficacy in controlling DP. Thus, this study is aimed at investigating the effect of moderate-intensity aerobic exercise before breakfast on the blood glucose level and glycemic variability in T2D patients with DP. Methods: A total of 20 T2D patients with DP confirmed via continuous glucose monitoring (CGM) participated in the current study. After collecting baseline measurements by CGM as a control, CGM was reinstalled and 30 minutes of moderate-intensity aerobic exercise was performed prior to breakfast. Dawn blood glucose increase, blood glucose levels, and glycemic variability were measured before and after exercise. Results: Dawn blood glucose increase (ΔGlu, 1.25 ± 0.84vs.2.15 ± 1.07, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs. 8.78 ± 1.09, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs. 8.78 ± 1.09, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs. 8.78 ± 1.09, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs. 8.78 ± 1.09, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs.2.15 ± 1.07, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs.2.15 ± 1.07, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs.2.15 ± 1.07, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16. Conclusions: Acute moderate-intensity aerobic exercise before breakfast reduced the morning rise of blood glucose in T2D patients, partially counteracting DP. Furthermore, exercise significantly reduced blood glucose fluctuations and improved blood glucose control throughout the day. We recommend that T2D patients with DP take moderate-intensity aerobic exercise before breakfast to improve DP and glycemic control.
... Studies by the Hvidore group and others [49][50][51][52] have demonstrated that glycaemic control between 11 and 18 years of age remains poor. This is mostly attributed to the normal physiological changes of puberty, as increased levels of growth hormone are responsible for overnight insulin resistance-also known as the "dawn phenomenon" [53]. ...
... Therefore, consistent research to clinically elucidate these effects and reflect new physiological responses is needed. In future, the model may be further improved to consider new physiological responses such as the dawn phenomenon (an abnormal elevated BGL in early morning) depending on circadian cycles (29). Moreover, the model has a great potential to be extended in various clinical situations before clinical trials. ...
Article
Full-text available
Although various basal-bolus insulin therapy (BBIT) protocols have been used in the clinical environment, safer and more effective BBIT protocols are required for glucose control in hospitalized patients with type 2 diabetes (T2D). Modeling approaches could provide an evaluation environment for developing the optimal BBIT protocol prior to clinical trials at low cost and without risk of danger. In this study, an in-silico model was proposed to evaluate subcutaneous BBIT protocols in hospitalized patients with T2D. The proposed model was validated by comparing the BBIT protocol and sliding-scale insulin therapy (SSIT) protocol. The model was utilized for in-silico trials to compare the protocols of adjusting basal-insulin dose (BBIT1) versus adjusting total-daily-insulin dose (BBIT2). The model was also used to evaluate two different initial total-daily-insulin doses for various levels of renal function. The BBIT outcomes were superior to those of SSIT, which is consistent with earlier studies. BBIT2 also outperformed BBIT1, producing a decreased daily mean glucose level and longer time-in-target-range. Moreover, with a standard dose, the overall daily mean glucose levels reached the target range faster than with a reduced-dose for all degrees of renal function. The in-silico studies demonstrated several significant findings, including that the adjustment of total-daily-insulin dose is more effective than changes to basal-insulin dose alone. This research represents a first step toward the eventual development of an advanced model for evaluating various BBIT protocols.
Article
Rebound hyperglycaemia (also termed Somogyi effect) is defined as hyperglycaemia caused by the release of counter-regulatory hormones in response to insulin-induced hypoglycaemia, and is widely believed to be common in diabetic cats. However, studies in human diabetic patients over the last quarter century have rejected the common occurrence of this phenomenon. Therefore, we evaluated the occurrence and prevalence of rebound hyperglycaemia in diabetic cats. In a retrospective study, 10,767 blood glucose curves of 55 cats treated with glargine using an intensive blood glucose regulation protocol with a median of five blood glucose measurements per day were evaluated for evidence of rebound hyperglycaemic events, defined in two different ways (with and without an insulin resistance component). While biochemical hypoglycaemia occurred frequently, blood glucose curves consistent with rebound hyperglycaemia with insulin resistance was confined to four single events in four different cats. In 14/55 of cats (25%), a median of 1.5% (range 0.32-7.7%) of blood glucose curves were consistent with rebound hyperglycaemia without an insulin resistance component; this represented 0.42% of blood glucose curves in both affected and unaffected cats. We conclude that despite the frequent occurrence of biochemical hypoglycaemia, rebound hyperglycaemia is rare in cats treated with glargine on a protocol aimed at tight glycaemic control. For glargine-treated cats, insulin dose should not be reduced when there is hyperglycaemia in the absence of biochemical or clinical evidence of hypoglycaemia. © ISFM and AAFP 2015.
Article
Aims Sensor augmented insulin pumps have become a powerful tool for managing type 1 diabetes (T1D). This study aimed to analyze the insulin pump configuration in users of predictive insulin suspension technology (PLGS). Methods T1D patients on insulin pumps with PLGS (Medtronic 640G®) were enrolled. Data was obtained from medical records and pump data was downloaded for 30 days. Basal insulin, bolus calculator parameters, and PLGS operation parameters were analyzed and compared with Time in Range, Time Below Range, and Time Above Range. Results 112 patients were included, with average TIR of 73,96 % and HbA1c 7,0 % and 25 months of follow-up. Basal insulin remained similar to initial doses, with an increase of 27 % for the Dawn phenomenon. The Carbohydrate ratio was slightly more aggressive. Insulin sensitivity was 17 % less stringent than initially programmed. No differences were observed in Time in Rage according to the number of basal, ratio, and sensitivity segments. Time of insulin suspension correlated directly with Time Bellow Range. Conclusions Patients with good metabolic control have basal insulin programming similar to their initiation doses with less aggressive sensitivity factors. Excessive suspension time determined by PLGS could be an expression of excess insulin and increased hypoglycemia risk.
Article
Full-text available
The traditional statistical analysis of notifications of adverse drug reactions in diabetic patients was complex and sparse. The data mining techniques –web graph and Kohonen networks model- allow us to identify drug-treated diabetic patients who suffer adverse reactions. Nonfatal severe metabolic disorders due to insulin glargine in women in Catalonia, and non-serious gastrointestinal metformin disorders in women between 65 and 74 years in Aragon are two characteristics profiles. Patients treated with three or more oral agents are at increased risk of suffering an adverse reaction.
Article
"Mild dysglycemia" in type 2 diabetes can be defined by the range of HbA1c levels≥6.5% (48mmol/mol) and<7% (53mmol/mol), which corresponds to when the risk for vascular complications begins to increase. This "mild dysglycemia" is characterized by both a dawn phenomenon (a spontaneous blood glucose rise in the early morning) and an excess of post-prandial glucose excursions in the absence of abnormal elevation in basal glucose, especially during nocturnal periods. This represents an intermediary stage between pre-diabetes (HbA1c≥5.7%, 39mmol/mol, and<6.5%, 48mmol/mol) and those who begin to show a steadily progressive worsening in basal glucose (HbA1c≥7%, 53mmol/mol). Should this relatively minor intermediate dysglycemic phase deserve more attention, that is the question. The now available incretin-based therapies, and more specifically the DPP-4 inhibitors provide the clinician with the possibility to reduce or eradicate both the dawn phenomenon and post-meal glucose excursions with minimal side effects. The availability of 24-h glycemic profiles in those with "mild dysglycemia" will help to describe their individual glycemic phenotype, based on which the early and appropriate life style changes and/or pharmacological interventions can be introduced. Copyright © 2014 Elsevier Inc. All rights reserved.
Chapter
The production and action of insulin are influenced by other hormones, such as growth hormone, corticosteroids, and 20atecholamines. Accordingly, disorders that result in over- or under-production of these hormones can disturb glucose homeostasis and lead to glucose intolerance or diabetes. Underlying endocrine dysfunction beyond insulin should be considered in all people presenting with diabetes and in individuals whose diabetes is proving difficult to control. Treating the underlying endocrine disorder is likely to improve glycemic control and potentially cure the diabetes. This chapter focuses on the main endocrine disorders that compromise glucose homeostasis.
Article
Full-text available
Introduction: The objective of this study was to compare differences in glucoregulation, frequency of hypoglycemic episodes, glucose variability and lipid profiles of inpatients with poorly regulated type 1 diabetes mellitus (T1DM) after evening versus morning glargine application. Methods: Eighteen patients with poorly regulated T1DM, glycated hemoglobin (Hba1c) levels ≥7% and frequent nocturnal and/or morning hypoglycemic episodes were included in this study. There was a 12-week screening phase where patients continued their usual insulin regimen and were encouraged to achieve optimal glycemic control; however, all patients maintained HbA1c values ≥7% and continued to have frequent nocturnal and/or morning hypoglycemic events and were therefore transitioned to morning application of insulin glargine for 12 weeks. The primary outcome was to investigate changes in HbA1c values 12 weeks after the transition. The secondary outcome was to evaluate the effect of transition on glucose variability, incidence of hypoglycemic episodes, insulin doses, lipid profile and weight. Data were analyzed using paired Student's t test and Pearson correlation. Results: After the transition, there was no significant change in total daily dose of basal insulin (p 0.114) and the average body weight remained unchanged, while significant reduction of HbA1c was present (8.02 ± 0.5 vs. 7.4 ± 0.3%) (p < 0.01) resulting in a decrease in nocturnal and daytime hypoglycemic episodes per month per person (p < 0.01). Parameters of glucose variability (glycemic standard deviations and J-index) were also improved after transition period (p < 0.01). As for the lipid profile, increase of high-density lipoprotein cholesterol and decrease of triglycerides (p < 0.01) were noticed, while other lipid parameters remained unaffected. Furthermore, insignificant association of basal insulin dose with HbA1c values regardless of the time of administration was observed. Conclusion: In patients with poorly regulated T1DM, transition to morning application of glargine improved glucoregulation (including a decrease in HbA1c, glucose variability and number of nocturnal hypoglycemic episodes), followed by favorable changes in lipid profile without affecting body weight. These effects were associated with the time of application, but not with the insulin dose.
Article
IntroductionAcromegalyCushing syndromePheochromocytomaOther endocrine conditions causing disturbance of glucose toleranceEndocrine disorders that associate with diabetesReferences
Article
A 32-year-old man presented in a coma |GCS (El, V2, M2) | due to hypoglycemic encephalopathy. Diffusion-weighted MRI (DWI), performed immediately after the patient lapsed into a coma, demonstrated high-intensity signal areas in the bilateral subcortex, including the corona radiata and caudate nucleus. While these signals, observed on MRI, transiently increased on day 3, they had decreased by day 7. On day 20, he showed recovery of consciousness, and the signals, observed on DWI, had completely disappeared by day 20. Three months later, he was discharged after activities of daily living, such as walking and conversation, had greatly improved. Herein, we present this diabetic patient with hypoglycemic encephalopathy, showing sequential DWI findings, i.e. the restricted high-intensity signal areas in the bilateral subcortex and their extinctions, to be very useful for predicting the functional outcomes of patients with severe hypoglycemia.
Article
Full-text available
Despite published studies on the use of insulin in diabetes, no satisfactory routine method for regulating the insulin dosage and the time of administration has yet evolved. Self-monitoring of blood glucose (SMBG) is recognized as a core component of diabetes self-management. However, there are many limitations to SMBG use in individuals with diabetes who are treated with intensive insulin regimens. Furthermore, persistent nocturnal hypoglycemia anxiety and neuropathically induced gastric palsy remain a major challenge in patients with high blood sugar values at night and frequent postprandial hypoglycemias. The “bathtub” curve describes a daily blood glucose profile in which blood sugar rises after dinner and does not drop to the target range until the high level is corrected in the morning. This case report addresses the challenges such a blood sugar course imposes on healthcare providers and researchers. We think it will contribute invaluable consideration for diabetes management and help to reduce related complications.
Preprint
Full-text available
Nocturnin (NOCT) is a rhythmically expressed protein that regulates metabolism under the control of circadian clock. It has been proposed that NOCT deadenylates and regulates metabolic enzyme mRNAs. However, in contrast to other deadenylases, purified NOCT lacks the deadenylase activity. To identify the substrate of NOCT, we conducted a mass spectrometry screen and report that NOCT specifically and directly converts the dinucleotide NADP ⁺ into NAD ⁺ and NADPH into NADH. Further, we demonstrate that the Drosophila NOCT ortholog, Curled, has the same enzymatic activity. We obtained the 2.7 Å crystal structure of the human NOCT·NADPH complex, which revealed that NOCT recognizes the chemically unique ribose-phosphate backbone of the metabolite, placing the 2′-terminal phosphate productively for removal. We provide evidence for NOCT targeting to mitochondria and propose that NADP(H) regulation, which takes place at least in part in mitochondria, establishes the molecular link between circadian clock and metabolism.
Article
Objectives: To better understand the dawn phenomenon in type 1 diabetes, we sought to determine its prevalence, timing and magnitude in studies specifically designed to assess basal insulin requirements in patients using insulin pumps. Methods: Thirty-three participants from 2 sensor-augmented insulin pump studies were analyzed. Twenty participants were obtained from a methodologically ideal semiautomated basal analysis trial in which basal rates were determined from repeated fasting tests (the derivation set) and 13 from an artificial pancreas trial in which duration of fasting was variable (the "confirmation" set). Prevalence was determined for the total cohort and for individual trials using the standard definition of an increase in insulin exceeding 20% and lasting ≥90 minutes. Among cases, time of onset and percent change in the magnitude of basal delivery were determined. Results: Seventeen participants (52%) experienced the dawn phenomenon (11 of 20 [55%] in the derivation set and 6 of 13 [46%] in the confirmation set). Time of onset was 3 AM (interquartile range [IQR], 3 to 4:15 AM) in the derivation set and 3 AM (IQR, 3 to 4 AM) in the confirmation set. The magnitude of the dawn phenomenon was a 58.1% (IQR, 28.8% to 110.6%) increase in insulin requirements in the derivation set and 65.5% (IQR, 45.6% to 87.4%) in the confirmation set. Conclusions: The dawn phenomenon occurs in approximately half of patients with type 1 diabetes; when present, it has predictable timing of onset (generally 3 AM) and a substantial, but highly variable, magnitude. These findings imply that optimization of glycemic control requires clinical emphasis on fasted overnight basal insulin assessment.
Article
Full-text available
Aims: We developed a quantitative systems pharmacology model to describe the effect of dapagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on glucose-insulin dynamics in type 2 diabetes mellitus (T2DM) patients and identified key determinants of treatment-mediated glycated hemoglobin (HbA1c) reduction. Materials and methods: Glycemic control during dapagliflozin treatment was mechanistically characterized by integrating components representing pharmacokinetics (PK), glucose-insulin homeostasis, renal glucose reabsorption, and HbA1c formation. The model was developed using PK, glucose, plasma insulin, and urinary glucose excretion (UGE) from a phase IIa dapagliflozin trial in patients with T2DM (NCT00162305). The model was used to predict dapagliflozin-induced HbA1c reduction; model predictions were compared to actual data from phase III trials (NCT00528879, NCT00683878, NCT00680745, and NCT00673231). Results: The integrated glucose-insulin-dapagliflozin (IGID) model successfully described plasma glucose and insulin levels, as well as UGE in response to oral glucose tolerance tests and meal intake. HbA1c reduction was also well predicted. The results show that dapagliflozin-mediated glycemic control is anticorrelated to steady-state insulin concentration and insulin sensitivity. Conclusions: The developed model framework is the first to integrate SGLT2 inhibitor mechanism of action with both short-term glucose-insulin dynamics and long-term glucose control (HbA1c). The results suggest that dapagliflozin treatment is beneficial in patients with inadequate glycemic control from insulin alone and this benefit increases as insulin control diminishes. NCT00162305, NCT00528879, NCT00683878, NCT00680745, and NCT00673231. This article is protected by copyright. All rights reserved.
Article
Objective Continuous subcutaneous insulin infusion (CSII) programming for an early morning increase in insulin delivery is frequently recommended to counteract the rise in glucose prior to breakfast (dawn phenomenon). However, both the effectiveness and safety of this approach have not been tested in the ambulatory setting. Using continuous glucose monitoring, we investigated the safety and effectiveness of early morning CSII programming for management of the dawn phenomenon in subjects with type 1 diabetes. Methods We conducted a controlled, observational, 8-month longitudinal study of type 1 diabetic patients (N = 40). Reproducibility of the dawn phenomenon was determined in subjects treated with multiple daily injections of insulin (n = 12) and those on CSII who did not program an early morning increase in insulin delivery (CSII non-programmers; n = 8). The effects of early morning CSII programming were determined by comparing rates of the dawn phenomenon and hypoglycemia in CSII nonprogrammers versus CSII users who programmed an early morning increase in insulin delivery (CSII programmers; n = 20). Results The dawn phenomenon occurred in all tested subjects to a variable extent (median rate, 56% of nights). CSII programming was not associated with a reduction in the occurrence of the dawn phenomenon (42%) compared to nonprogrammers (48%) (P = .47) nor in the magnitude of the dawn phenomenon. Hypoglycemia occurred more frequently in the CSII programmers (37%) compared with nonprogrammers (18%) (P = .001). Conclusion The dawn phenomenon occurs unpredictably; therefore, early morning CSII programming for a fixed increase in early morning insulin delivery is ineffective and may be hazardous to the patient. (Endocr Pract. 2014;20:1290-1296)
Article
Aims: To compare meal-time glycaemia in adults with type 1 diabetes mellitus (T1D) managed with multiple daily injections (MDI) vs. insulin pump therapy (IPT), using self-monitoring blood glucose (SMBG), following diabetes education. Methods: Adults with T1D received carbohydrate-counting education and a bolus calculator: MDI (Roche Aviva Expert) and IPT (pump bolus calculator). All then wore 3-weeks of masked-CGM (Enlite, Medtronic). Meal-times were assessed by two approaches: 1) Set time-blocks (breakfast 06:00-10:00hrs; lunch 11:00-15:00hrs; dinner 17:00-21:00hrs) and 2) Bolus-calculator carbohydrate entries signalling meal commencement. Post-meal masked-CGM time-in-range (TIR) 3.9-10.0 mmol/L was the primary outcome. Results: MDI(n = 61) and IPT (n = 59) participants were equivalent in age, sex, diabetes duration and HbA1c. Median (IQR) education time provided did not differ (MDI: 1.1 h (0.75, 1.5) vs. IPT: 1.1 h (1.0, 2.0); p = 0.86). Overall, daytime (06:00-24:00hrs), lunch and dinner TIR did not differ for MDI vs. IPT participants but was greater for breakfast with IPT in both analyses with a mean difference of 12.8%, (95 CI 4.8, 20.9); p = 0.002 (time-block analysis). Conclusion: After diabetes education, MDI and IPT use were associated with similar day-time glycemia, though IPT users had significantly greater TIR during the breakfast period. With education, meal-time glucose levels are comparable with use of MDI vs. pumps.
Article
Full-text available
Background Estimation of insulin sensitivity factor (ISF) is essential for correction insulin doses calculation. This study aimed to assess real-life ISF among children and adolescents with type 1 diabetes using ultra-long-acting basal insulin analogs and to detect factors associated with ISF among those patients. Methods This prospective observational study was conducted at Sohag University Hospital, Egypt, and included 93 participants aged 6–18 years, diagnosed with T1DM for at least 1 year and using insulin glargine 300 Units/mL or insulin degludec 100 Units/mL as basal insulin. The ISF, insulin-to-carbohydrate ratio (ICR) and insulin doses were initially assessed then adjusted as required. The participants were regularly contacted throughout the follow-up period. Glycemic control parameters were assessed after 3 months. Results The ISF showed diurnal variation with higher correction dose requirements for the morning than for the rest of the day ( p < 0.001). This pattern of diurnal variation was found in participants with different pubertal stages and in participants using either type of ultra-long acting basal insulin analogs. There was no significant difference between the ISF calculated according to the 1800 rule [1800/Total daily insulin dose (TDD)] and the morning ISF ( p = 0.25). The 1800 rule-calculated ISF was significantly lower than the actual ISF for the afternoon ( p < 0.001) and the evening ( p < 0.001). ISF at different times of the day were significantly correlated with age, body mass index, pubertal stage, diabetes duration, TDD, and ICR. Multiple regression analysis revealed that ICR was the most significant factor associated with ISF. Linear regression analysis revealed that the ISF (in mg/dL) for any time of the day could be estimated as 5.14 × ICR for the same time of the day (coefficient = 5.14, 95% confidence interval: 5.10–5.19, R ² = 0.95, p < 0.001). Conclusion Diurnal variation of ISF that had to be considered for proper calculation of correction doses. This diurnal variation was found in children and adolescents with different pubertal stages. The 1800 rule was appropriate for the morning correction doses but not in the afternoon or the evening. The TDD and the ICR could be used for ISF estimation.
Article
Overview: As children with diabetes enter adolescence, the physical and psychological changes of puberty add to the challenges of disease management. This often leads to increased stress for both parent and child and to poor overall glucose control with potential short- and long-term complications. During this period of transition, nurses play a central role in teaching patients and their families about the effects of puberty on insulin sensitivity and glucose metabolism, and in discussing how the emotional and behavioral changes associated with this challenging time can affect diabetes management.
Article
Full-text available
To test the hypothesis that nocturnal hypoglycemia causes postprandial hyperglycemia the next day (the Somogyi phenomenon) in patients with insulin-dependent diabetes mellitus (IDDM), we studied 10 moderately well controlled patients, who were on their usual therapeutic regimens, from 2000 to 2000 on three occasions. On a control day, samples were obtained without intervention. On another day, nocturnal hypoglycemia was prevented (by intravenous infusion of glucose, if necessary, from 2200 to 0400 to keep plasma glucose levels at greater than 5.6 mM). On another day, nocturnal hypoglycemia was induced (by stepped intravenous insulin infusions between 2200 and 0200 to reduce plasma glucose levels to less than 2.8 mM). After nocturnal hypoglycemia (1.9 +/- 0.2 mM), fasting (0800), morning (0800-1100), afternoon (1200-1500), evening (1600-2000), and entire-day (0800-2000) plasma glucose concentrations were no higher than those after prevention of nocturnal hypoglycemia or sampling only. On the control day, fasting and daytime plasma glucose levels were directly related to the preceding 2200 (r = 0.723, P less than 0.02, and r = 0.762, P = 0.01, respectively) and nocturnal nadir (r = 0.714, P less than 0.02, and r = 0.728, P less than 0.02) plasma glucose concentrations. Daytime plasma glucose levels were unrelated to peak nocturnal plasma glucagon, epinephrine, norepinephrine, growth hormone, or cortisol concentrations. We conclude that nocturnal hypoglycemia does not appear to cause clinically important daytime hyperglycemia in patients representative of most patients with IDDM.
Article
Full-text available
We examined the clinical relevance of a rise in fasting blood glucose (BG) between 0300 and 0600 in 97 patients with insulin-dependent diabetes mellitus (IDDM) receiving sequentially conventional (CT) and basal-bolus (BBIT) insulin therapies and assessed the impact of one potential causal factor, i.e., posthypoglycemic hyperglycemia, with 231 BG profiles (97 during CT, 134 during BBIT) in which BG was measured every 3 h over a 24-h period. A rise in BG between 0300 and 0600 occurred in 157 of 231 (68%) profiles. The mean magnitude of this rise was 56 +/- 39 mg/dl and was lower (P less than .05) during BBIT (48 +/- 35 mg/dl, n = 97) than CT (62 +/- 43 mg/dl, n = 97). A dawn rise (between 0300 and 0600) greater than 50 mg/dl occurred in 40 of 97 (41%) profiles during CT and 26 of 97 (27%) during BBIT (P less than .05). When all profiles were grouped according to the magnitude of this rise in BG, the mean daytime BG (from 0900 to 1800) was higher (P less than .05) after an 0300-0600 BG rise greater than 50 mg/dl compared with groups of profiles showing either a fall in BG or a rise less than 50 mg/dl; a rise in BG between 0300 and 0600 correlated (r = .38, P less than .0001) with the subsequent mean daytime BG. Nocturnal hypoglycemia (BG less than 60 mg/dl) recorded at 2400 and/or 0300 occurred in 57 of 231 (25%) profiles.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Full-text available
We analyzed 216 overnight blood glucose profiles (samples at 2100, 0300, and 0700 h) in 75 consecutive patients with diabetes mellitus primarily to assess the impact of nocturnal hypoglycemia on morning hyperglycemia and secondarily to assess the frequency and magnitude of a night-to-morning increase in glucose levels in a clinical context. A dawn phenomenon (an 0300 to 0700 h increment in blood glucose) was rather uncommon in our patients (about one-third of profiles), was readily demonstrable in groups of patients only when nocturnal glucose levels were low (less than or equal to 50 mg/dl) or normal (51-100 mg/dl), and was generally not of great magnitude (mean 0700 h glucose levels of 114 mg/dl after 0300 h values of less than or equal to 100 mg/dl). Nocturnal hypoglycemia (0300 h blood glucose of less than or equal to 50 mg/dl, 7% of profiles) was followed by significant increments in blood glucose. However, the 0700 h glucose values averaged only 113 mg/dl and ranged up to only 172 mg/dl. Clearly, the magnitude of this Somogyi phenomenon was not great. Mean glucose levels were not higher at 1100, 1600, or 2100 h the day after nocturnal hypoglycemia than those at the same times the day before hypoglycemia. Thus, nocturnal hypoglycemia does not commonly result in major morning, or daytime, hyperglycemia in patients with diabetes mellitus sampled while using their usual therapeutic regimens.
Article
Full-text available
The dawn phenomenon, a tendency for glucose to rise between 0500 and 0800 h in subjects with diabetes, is also reflected as an increase in insulin required to maintain normoglycemia during closed-loop insulin infusion. Individuals without diabetes have minimal or absent rises in early morning glucose. To test the hypothesis that the absence of early morning glucose increases in subjects without diabetes is due to an increase in insulin levels, we measured insulin levels from 2400 to 0800 h in four male and two female volunteers. Subjects were on an unrestricted diet with three main meals and one bedtime snack at 2100 h. Blood samples were collected continuously in hourly pools by a constant-rate withdrawal pump. We observed the following: (1) hourly integrated concentration of glucose was stable from 2400 to 0800 h (range of mean plasma values, 94.5-97.3 mg/dl), and (2) hourly integrated concentration of insulin increased from the 0300-0400 (4.6 microU/ml) to the 0700-0800-h pool (6.2 microU/ml) (P less than 0.05). The observed increase in insulin in the early morning hours despite stable levels of glucose indicates a temporally increased insulin need in nondiabetic individuals similar to that found in individuals with diabetes. The mechanism underlying this increased insulin need may be similar in diabetes and nondiabetes, with the ensuing rise in glucose being dependent on the availability of compensatory insulin.
Article
Full-text available
Eleven insulin-dependent (type I) diabetic subjects were studied during a 24-h period to assess intraday blood glucose (BG) variation and related free insulin (FI) levels. Ten patients exhibited the dawn phenomenon, a rise in early morning fasting blood glucose (123 +/- 81.1 m/dl; mean +/- SD). This increase was positively and significantly correlated with the morning postprandial BG peak (r = 0.723; P = 0.012). FI/BG ratios were highest during the night (0.717 and 0.666 at 2200 and 0400 h, respectively) and lowest during the early morning (0.294 at 0800 h) (P less than 0.01). Three of the four observed hypoglycemic episodes occurred during the period when free insulin levels were high relative to BG. We conclude that the dawn phenomenon contributed directly and significantly to the BG maximum and indirectly, in some cases, to nocturnal hypoglycemia. It thus played an important role in the intraday blood glucose variation of such patients.
Article
Full-text available
Overnight basal insulin requirements to maintain euglycemia were determined in five insulin-dependent diabetic subjects using a closed-loop insulin infusion system. A significant increase in hourly insulin requirements occurred between 0600 h and 0900 h as compared with 0100 h-0600 h. Although the increased insulin requirement was coincident with only the physiologic diurnal increase in plasma cortisol, the oral administration of the 11-beta hydroxylase inhibitor, metyrapone, decreased only the total overnight (0100 h-0900 h) basal insulin requirement, but not the early morning (0600 h-0900 h) rise in insulin required to maintain euglycemia. It would appear that although cortisol is an important counterregulatory factor, its diurnal elevation cannot account for the increase in early morning basal insulin requirements to maintain euglycemia in insulin-dependent diabetes.
Article
Full-text available
To clarify the involvement of IGF binding protein (IGFBP)-1 in the dawn rise in plasma glucose and in the overall glycemic control in patients with IDDM. Seventy patients with IDDM were divided into three groups according to pubertal development. Blood samples were obtained for measuring plasma glucose, IGFBP-1, and free insulin at 2200, 0500, and 0700 over a 2-day period. Levels of HbA1c, IGF-1, and IGFBP-3 were determined at 0700. Urinary growth hormone (GH) was collected overnight. To examine its frequency, the dawn phenomenon was defined on the basis of the following: 1) change in plasma glucose from 0500 to 0700, 2) plasma glucose level at 0700, and 3) no antecedent hypoglycemia. There was a statistically significant link between the dawn changes in plasma glucose and IGFBP-1 (r = 0.37, P < 0.01). The former was not related to the change in free insulin or to the overnight urinary GH level. In stepwise regression analyses, plasma glucose at 0700 = 0.03 IGFBP-1 (P < 0.01) + 0.525 HbA1c (P < 0.01) + 3.696 (R2 = 51%). Approximately half of the patients in each group exhibited the dawn phenomenon; 38% of patients with HbA1c < 8% also showed the dawn phenomenon. We have demonstrated a statistically significant link between the morning risk in IGFBP-1 and plasma glucose. The free fraction of IGF-1 modulated by acute changes in IGFBP-1 may play a direct role. The dawn phenomenon may occur regardless of pubertal stage or glycemic control in children and adolescents with IDDM.
Article
Full-text available
We examined the effect of glycemic control of NIDDM on counterregulatory hormone responses to hypoglycemia and compared the effect with that seen in patients with IDDM. Eleven subjects with NIDDM and eight age- and weight-matched control subjects and ten subjects with IDDM and ten age- and weight-matched control subjects were studied. All subjects underwent a stepped hypoglycemic-hyper-insulinemic clamp study during which plasma glucose levels were lowered in a stepwise manner from 5.0 to 2.2 mmol/l in steps of 0.6 mmol/l every 30 min. Counterregulatory hormones (epinephrine, norepinephrine, glucagon, ACTH, cortisol, and growth hormone [GH]) were measured, and a symptom survey was administered during the last 10 min of each 30-min interval. The threshold for release of epinephrine, norepinephrine, ACTH, and cortisol occurred at higher plasma glucose levels in NIDDM than in IDDM patients (P < 0.05-0.01). The glucose threshold for release of epinephrine and norepinephrine correlated with glycemic control as measured by glycosylated hemoglobin (P < 0.05-0.01). However, for a given level of glycemic control, the threshold for release of epinephrine and norepinephrine occurred at a higher glucose level in NIDDM versus IDDM patients (P < 0.05-0.01). At the nadir level of hypoglycemia, glucagon, ACTH, and cortisol levels were all higher in NIDDM compared with IDDM subjects, whereas GH levels were lower. Glycemic control alters counterregulatory responses to hypoglycemia in NIDDM as has been previously reported in IDDM. However, at similar levels of glycemic control, NIDDM patients release counterregulatory hormones at a higher plasma glucose level than patients with IDDM. In addition, subjects with NIDDM maintain their glucagon response to hypoglycemia. These data suggest that patients with NIDDM may be at reduced risk of severe hypoglycemia when compared with a group of IDDM patients in similar glycemic control, thus providing a more favorable risk-benefit ratio for intensive diabetes therapy in NIDDM.
Article
Full-text available
The objective of this study was to evaluate whether first-degree relatives (FDRs) of patients with type 2 diabetes had abnormal circadian insulin secretion and, if so, whether this abnormality affected their glucose metabolism. Six African-American FDRs with normal glucose tolerance and 12 matched normal control subjects (who had no family history of diabetes) were exposed to 48 h of hyperglycemic clamping (approximately 12 mmol/l). Insulin secretion rates (ISRs) were determined by deconvolution of plasma C-peptide levels using individual C-peptide kinetic parameters. Detrending and smoothing of data (z-scores) and computation of autocorrelation functions were used to identify ISR cycles. During the initial hours after start of glucose infusions, ISRs were approximately 60% higher in FDRs than in control subjects (585 vs. 366 nmol/16 h, P < 0.05), while rates of glucose uptake were the same (5.6 mmol x kg(-1) x h(-1)), indicating that the FDRs were insulin resistant. Control subjects had well-defined circadian (24 h) cycles of ISR and plasma insulin that rose in the early morning, peaked in the afternoon, and declined during the night. In contrast, FDRs had several shorter ISR cycles of smaller amplitude that lacked true periodicity. This suggested that the lack of a normal circadian ISR increase had made it impossible for the FDRs to maintain their compensatory insulin hypersecretion beyond 18 h of hyperglycemia. As a result, ISR decreased to the level found in control subjects, and glucose uptake fell below the level of control subjects (61 vs. 117 micromol x kg(-1) x min(-1), P < 0.05). In summary, we found that FDRs with normal glucose tolerance had defects in insulin action and secretion. The newly recognized insulin secretory defect consisted of disruption of the normal circadian ISR cycle, which resulted in reduced insulin secretion (and glucose uptake) during the ascending part of the 24 h ISR cycle.
Article
Full-text available
To study the pharmacodynamic properties of the subcutaneously injected long-acting insulin analog HOE901 (30 microg/ml zinc) in comparison with those of NPH insulin and placebo. In this single-center double-blind euglycemic glucose clamp study, 15 healthy male volunteers (aged 27 +/- 4 years, BMI 22.2 +/- 1.8 kg/m2) received single subcutaneous injections of 0.4 U/kg body wt of HOE901, NPH insulin, or placebo on 3 study days in a randomized order. The necessary glucose infusion rates (GIRs) to keep blood glucose concentrations constant at 5.0 mmol/l were determined over a 30-h period after administration. The injection of HOE901 did not induce the pronounced peak in metabolic activity observed with NPH insulin (GIRmax 5.3 +/- 1.1 vs. 7.7 +/- 1.3 mg x kg(-1) x min(-1)) (P < 0.05); after an initial rise, metabolic activity was rather constant over the study period. This lack of peak was confirmed by a lower glucose consumption in the first 4 h after injection (area under the curve from 0 to 4 h [AUC(0-4 h)] 1.02 +/- 0.34 vs. 1.48 +/- 0.34 g/kg) (P < 0.001) with HOE901, as compared with NPH insulin. In this single-dose study, the metabolic effect measured over a period of 30 h was lower with HOE901 than with NPH insulin (AUC(0-30 h) 7.93 +/- 1.82 vs. 9.24 +/- 1.29 g/kg) (P < 0.05). This study shows that the soluble long-acting insulin analog HOE901 induces a smoother metabolic effect than NPH insulin, from which a better substitution of basal insulin requirements may follow.
Article
ABSTRACT The effect of growth hormone (GH) on the glucose homeostasis following nocturnal hypoglycemia was studied between 4 a.m. and noon in eight male patients with insulin-dependent diabetes mellitus (IDDM) by a somatostatin (250 μg/h)-insulin (0.4 mU/kg/min)-glucose (6 mg/kg/min)-infusion test (SIGIT). The patients participated in two experiments in which hypoglycemia at 4 a.m. was induced by i.v. insulin (1.5 mU/kg/min). In both experiments the endogenous secretion of GH was suppressed by somatostatin (250 μg/h) and glucagon (0.5 ng/kg/min) was given as substitute for the somatostatin-induced suppression of endogenous glucagon secretion. GH (20 mU/kg/h) or saline was given for 60 min from nadir blood glucose in random order. Mean nadir glucose values were the same in both studies (1.7 ± 0.2 vs. 1.7 ± 0.1 mmol/l) and no differences were registered in plasma-free insulin, glucagon and the responses of adrenaline and Cortisol to hypoglycemia. The infusion of GH resulted in plasma GH levels of about 50 μg/l at the end of the infusion, thereafter decreasing to low or immeasurable levels within 2 hours. Infusion of GH evoked a marked hyperglycemia within 4 hours. It is concluded that when hypoglycemia is accompanied by a transient increase in plasma GH, insulin resistance occurs after a lag period of approximately 4 hours and that this effect persists for at least another 4 hours.
Article
The effect of glycaemic control on the early morning plasma glucose rise, 'the dawn phenomenon', was assessed in two matching diabetic patient groups each comprising five NIDDM and two IDDM patients per group, who were otherwise considered to be in poor (HbA1 = 11.2 +/- 0.6%) or good (HbA1 = 7.6 +/- 0.2%) glycaemic control. Hourly plasma concentrations of glucose, insulin, glucagon, cortisol, and growth hormone were measured between 03.00 and 09.00 h. In all the poorly controlled diabetic patients the mean rise in plasma glucose between 06.00-08.00 and 03.00 h was greater than or equal to 1.0 mmol/l. In contrast, the plasma glucose increment was less than 1.0 mmol/l in the well controlled diabetics. The overnight mean insulin levels in the poor and well controlled patient groups were 19.3 +/- 0.5 and 25.0 +/- 0.6 mU/l (P less than 0.001) respectively. Glucagon, cortisol, and growth hormone levels in the early morning showed no significant differences between the two groups. The decline in plasma insulin from 03.00 to 08.00 h and mean cortisol level between 03.00 and 06.00 h were both significantly correlated with the increase in plasma glucose between 03.00 and 08.00 h. We concluded that an increase of 1.0 mmol/l or more in plasma glucose during the early morning is of clinical importance.
Article
To determine the role of growth hormone in overnight insulin requirements and lipolysis, five patients with chronic growth hormone deficiency and Type 1 (insulin-dependent) diabetes mellitus and six control patients with diabetes were each studied on two separate nights. Insulin was infused at a variable rate throughout one night to maintain euglycaemia and fixed at 04.00 hours on another. During the variable infusion, euglycaemia was maintained in control patients by a 36% increase in insulin infusion rate between 03.00 and 08.00 hours while a 46% decrease in the rate was required in growth hormone deficient patients (p less than 0.02). Despite this difference, mean free insulin values were equivalent. This finding is suggestive of increased insulin clearance in growth hormone sufficient patients. Glucose levels rose in control and fell in growth hormone deficient patients when insulin infusion rates were fixed at 04.00 hours. Glycerol production and non-esterified fatty acid concentrations were significantly lower in the growth hormone deficient diabetic patients, p less than 0.001, and when normalized with a heparin infusion, had no effect on insulin requirements. We conclude that: (1) growth hormone contributes to the development of the "dawn phenomenon," possibly by increasing insulin clearance (2) growth hormone helps sustain nocturnal lipolysis in Type 1 diabetes and (3) non-esterified fatty acids are not involved in the dawn phenomenon.
Article
We have determined the consequences of insulin-like growth factor-binding protein-1 (IGFBP-1) administration alone and in combination with insulin-like growth factor-I (IGF-I). Human recombinant IGF-I, infused as a bolus into male Wistar rats, induced a fall in plasma glucose to 72 +/- 3% of baseline 15 min after injection. Co-infusion of equimolar concentrations of human IGFBP-1 abolished the IGF-I-induced fall (P less than 0.001). Injection of IGFBP-1 alone caused a rise in plasma glucose levels (P less than 0.002). The half life of human IGFBP-1, measured using a primate-specific RIA, was 12.5 +/- 0.7 min and was not influenced by the co-infusion of IGF-I. This study demonstrates that, in the rat, human IGFBP-1 blocks the hypoglycemic response to intravenous IGF-I and increases blood glucose levels when administered alone. Since IGFBP-1 concentrations are dependent on metabolic status, we suggest that fluctuating IGFBP-1 levels might modulate the hypoglycemic activity of unbound IGFs in the circulation.
Article
We have measured fasting 0800 h insulin-like growth factor binding proteins (IGFBP)-1 and IGFBP-3, in 52 diabetic adolescents and 74 puberty-matched control subjects with short stature and normal hormonal status. We have also measured overnight hourly profiles of IGFBP-1, glucose, free insulin, and GH in 12 of the diabetic adolescents. With advancing age and pubertal status, IGFBP-1 declined and IGFBP-3 increased significantly in the control, but not the diabetic group. Fasting IGFBP-1 levels were elevated 4-fold compared to controls. Median IGFBP-3 was significantly lower in the diabetic compared to the control group in pubertal stages III and V. Elevated IGFBP-1 was significantly correlated with metabolic control in poorly controlled subjects (mean 12-month glycosylated haemoglobin greater than 8.5%). In the overnight profiles, mean hourly IGFBP-1 was inversely related to insulin, but not glucose. As free insulin levels declined, IGFBP-1 rose, associated with rising predawn blood sugars. The integrated 3-h IGFBP-1 value (0500-0800 h) was significantly correlated with the corresponding glucose integrated value. IGFBP-1 area under the curve for the whole overnight profile was significantly correlated with glycosylated hemoglobin in 11 of the 12 subjects. IGFBP-1 from diabetic adolescents has been shown to inhibit IGF-I bioactivity. We postulate that IGFBP-1 may have a role in growth impairment of poorly controlled diabetes and may contribute to the dawn phenomenon.
Article
Growth hormone (GH) counteracts in general the effects of insulin on glucose and lipid metabolism, but shares protein anabolic properties with insulin. Under physiological circumstances GH does not affect total glucose turnover directly. There is however evidence that GH acutely decreases glucose oxidation (secondary to an increase in lipid oxidation) and suppresses muscle uptake of glucose, suggesting that GH redistributes glucose fluxes into a non-oxidative pathway, which could be a build up of glycogen depots through gluconeogenesis. Since GH secretion is inhibited in the fed state these actions are mainly important in the postprandial or fasting state. Under pathological conditions of GH excess (e.g. acromegaly, poorly controlled tp. 1 diabetes or high dose GH treatment) the diabetogenic actions of GH become apparent. In these patients increased endogenous glucose production, decreased muscle glucose uptake and rising blood glucose levels are observed. In patients with intact beta-cell function these changes are counterbalanced by hyperinsulinemia--such hyperinsulinemia may in the long term induce increased cardiovascular morbidity and mortality ('Reavens syndrome X'). When stimulated with insulin these patients exhibit insulin resistance at the liver, in adipose tissue and in muscle. Few elaborate studies on the effects of GH on glucose metabolism in GH deficient patients have been conducted. These patients are hypersensitive to the actions of insulin on glucose metabolism and there is some evidence that when GH initially is given to such patients in the GH deprived state, paradox insulin-like effects of GH may be observed. Whether this may relate to increased activity of insulin-like growth factors is unsettled.
Article
In 114 subjects with Type 1 (insulin-dependent) diabetes mellitus the nocturnal insulin requirements to maintain euglycaemia were assessed by means of i.v. insulin infusion by a Harvard pump. The insulin requirements decreased after midnight to a nadir of 0.102 +/- 0.03 mU.kg-1.min-1 at 02.40 hours. Thereafter, the insulin requirements increased to a peak of 0.135 +/- 0.06 mU.kg-1.min-1 at 06.40 hours (p less than 0.05). The dawn phenomenon (increase in insulin requirements by more than 20% after 02.40 hours lasting for at least 90 min) was present in 101 out of the 114 diabetic subjects, and its magnitude (% increase in insulin requirements between 05.00-07.00 hours vs that between 01.00-03.00 hours) was 19.4 +/- 0.54% and correlated inversely with the duration of diabetes (r = -0.72, p less than 0.001), but not with age. The nocturnal insulin requirements and the dawn phenomenon were highly reproducible on three separate nights. In addition, glycaemic control, state of counterregulation to hypoglycaemia and insulin sensitivity all influenced the magnitude of the dawn phenomenon as follows. In a subgroup of 84 subjects with Type 1 diabetes, the multiple correlation analysis showed that not only duration of diabetes (t = -9.76, p less than 0.0001), but also % HbA1 significantly influenced the magnitude of the dawn phenomenon (t = 2.03, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
We have investigated the relation between nocturnal insulin requirements and nocturnal growth hormone (GH) release in 26 diabetic adolescents at various puberty stages and have examined the effect of nocturnal GH suppression on pre-breakfast insulin requirement. In all the studies, euglycaemia was maintained overnight using a computer-calculated variable-rate insulin infusion, and 15-min blood samples were collected for GH assay. During initial clamp studies, insulin infusion rates were greater from 0500-0800 h (15.22 +/- 0.95 mU/kg/h, mean +/- SEM) than from 0100-0400 h (12.42 +/- 0.84 mU/kg/h, P less than 0.001). The increase in insulin infusion rate correlated with mean overnight GH concentration (r = 0.68, P less than 0.001), and was maximal at puberty stage 3 in both sexes. In seven of the subjects, a second identical clamp was performed following administration of 100 mg oral pirenzepine. During these studies, mean overnight GH levels were reduced by 11-85%, from 17.6 +/- 1.6 to 7.5 +/- 2.2 mU/l; P less than 0.01. Insulin requirements were not significantly different between the periods 0100-0400 and 0500-0800 h during these studies, and the reduction in pre-breakfast (0500-0800 h) insulin requirement when compared with the baseline studies correlated with the fall in GH secretion (rs = 0.82, P less than 0.01). The dawn increase in insulin requirement in adolescents with IDDM is related to the overnight GH secretion during puberty, and pre-breakfast insulin requirement can be reduced by suppressing nocturnal GH release.
Article
The aim of the present studies was to test the hypothesis that the dawn phenomenon in Type 1 (insulin-dependent) diabetes mellitus is due to a decrease in insulin sensitivity caused by nocturnal spikes of growth hormone. Twelve subjects with Type 1 diabetes were studied on two different occasions, from 24.00 to 02.00 hours, and from 06.00 to 08.00 hours with the euglycaemic clamp technique at two plasma free insulin levels (approximately 25 mU/l, n = 7; approximately 80 mU/l, n = 5). To eliminate the confounding factor of insulin waning of previous Biostator studies, prior to clamp experiments the diabetic subjects were infused with i.v. insulin by means of a syringe pump according to their minute-to-minute insulin requirements. Insulin sensitivity decreased at dawn as compared to the early night hours (approximately 30% increase in the rate of hepatic glucose production, approximately 25% decrease in the rate of peripheral glucose utilisation). Plasma insulin clearance did not change overnight. In seven Type 1 diabetic subjects, suppression of nocturnal spikes of growth hormone secretion by somatostatin during basal glucagon and growth hormone replacement resulted in complete abolition of the increased rate of hepatic glucose production at dawn. Replacement of nocturnal spikes of growth hormone faithfully reproduced the increase in hepatic glucose production at dawn of the control study.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The early-morning increase in insulin requirements of patients with insulin-dependent diabetes mellitus (IDDM) has been referred to as the "dawn phenomenon." To determine the roles of growth hormone levels and sympathoadrenal activity in this phenomenon, we studied six subjects with IDDM on four occasions during a constant overnight infusion of insulin. In control experiments (infusion of insulin alone), plasma glucose increased from 98 +/- 5 mg per deciliter at midnight to 225 +/- 36 at 8:00 a.m. (P less than 0.001), glucose production increased by 65 per cent (P less than 0.001), and glucose clearance decreased by 50 per cent (P less than 0.001). When nocturnal surges in growth hormone secretion were prevented by infusion of somatostatin plus replacement glucagon, neither plasma glucose levels nor glucose production increased significantly, and glucose clearance did not decrease. When nocturnal surges in growth hormone secretion were simulated by hourly intravenous injections of growth hormone (15 to 100 micrograms) during infusion of somatostatin and glucagon, plasma glucose levels and glucose production increased and glucose clearance decreased to values observed in control experiments. During combined alpha- and beta-adrenergic blockade (phentolamine and propranolol), values for plasma glucose, glucose production, and glucose utilization were not significantly different from those in control experiments. Increases in plasma glucose were significantly correlated with peak plasma growth hormone concentrations (r = 0.58, P less than 0.01). We conclude that nocturnal surges in growth hormone secretion are primarily responsible for the dawn phenomenon in patients with IDDM.
Article
Current evidence indicates that resistance to insulin due to nocturnal secretion of growth hormone plays an important role in the Dawn phenomenon and that day-to-day variability in growth hormone secretion makes this condition difficult to manage. We therefore assessed the effect of a long-acting somatostatin analog (L363,586) on overnight plasma glucose and growth hormone levels in six patients with insulin-dependent diabetes mellitus. The analog (600 micrograms) was administered intranasally at bedtime to determine whether the inconvenience of an additional injection could be avoided. Compared to control experiments, in which saline was administered intranasally, overnight increases in plasma glucose concentrations were reduced in all subjects by nearly 70% (48 +/- 19 v 148 +/- 26 mg/dL, P less than .01), plasma growth hormone was maintained at basal levels throughout the night (less than 2 v 8 to 12 ng/mL, P less than .01), and the analog was well tolerated. We conclude that pharmacologic blockade of growth hormone secretion may be a helpful approach to management of the Dawn phenomenon when it cannot be done safely and effectively by adjusting insulin doses.
Article
The effect of growth hormone (GH) on the glucose homeostasis following nocturnal hypoglycemia was studied between 4 a.m. and noon in eight male patients with insulin-dependent diabetes mellitus (IDDM) by a somatostatin (250 micrograms/h)-insulin (0.4 mU/kg/min)-glucose (6 mg/kg/min)-infusion test (SIGIT). The patients participated in two experiments in which hypoglycemia at 4 a.m. was induced by i.v. insulin (1.5 mU/kg/min). In both experiments the endogenous secretion of GH was suppressed by somatostatin (250 micrograms/h) and glucagon (0.5 ng/kg/min) was given as substitute for the somatostatin-induced suppression of endogenous glucagon secretion. GH (20 mU/kg/h) or saline was given for 60 min from nadir blood glucose in random order. Mean nadir glucose values were the same in both studies (1.7 +/- 0.2 vs. 1.7 +/- 0.1 mmol/l) and no differences were registered in plasma-free insulin, glucagon and the responses of adrenaline and cortisol to hypoglycemia. The infusion of GH resulted in plasma GH levels of about 50 micrograms/l at the end of the infusion, thereafter decreasing to low or immeasurable levels within 2 hours. Infusion of GH evoked a marked hyperglycemia within 4 hours. It is concluded that when hypoglycemia is accompanied by a transient increase in plasma GH, insulin resistance occurs after a lag period of approximately 4 hours and that this effect persists for at least another 4 hours.
Article
A dawn rise of plasma glucose (PG) and/or insulin, the 'dawn phenomenon', has been commonly reported in treated diabetic patients and normal subjects. To evaluate the effect of treatment on this phenomenon in non-insulin-dependent diabetics (NIDDMs), PG, C peptide, immunoreactive insulin (IRI), growth hormone (GH), cortisol, epinephrine, and norepinephrine were measured hourly between 24.00 and 09.00 h in 17 newly diagnosed untreated NIDDMs (group 1). The study was repeated in 11 patients after a year of treatment (group 2). The PG levels did not change significantly at any time from 03.00 to 08.00 h in group 1 but increased continuously from 6.7 +/- 0.5 mmol/l at 04.00 h to 7.8 +/- 0.5 mmol/l at 08.00 h (P less than 0.01) in group 2. IRI and C peptide decreased significantly after 07.00 h in both groups. GH and catecholamine changes were similar in group 1 and group 2. Cortisol levels showed a nadir at 02.00 h and a peak after 07.00 h in both groups. Our results demonstrate no dawn rise of mean PG, IRI and C peptide in newly diagnosed untreated NIDDMs but a significant rise of PG in the early morning period in NIDDMs after a year of treatment with diet alone and diet plus sulphonylureas. Therefore other factors such as treatment and/or duration of the diabetes may play an important role in the pathogenesis of the dawn phenomenon.
Article
In order to reassess the role of growth hormone in the dawn phenomenon, we studied eight C-peptide negative diabetic adolescents, who are likely to exhibit important nocturnal growth hormone surges. The insulin infusion rate necessary to maintain euglycaemia was predetermined in each patient from 22.00 hours to 01.00 hours, and then kept constant until 08.00 hours resulting in stable free insulin levels. Blood glucose rose from 4.3 +/- 0.7 mmol/l at 01.00 hours to 7.1 +/- 1.1 mmol/l at 08.00 hours (p less than 0.01) secondary to an increased hepatic glucose production. All the subjects presented an important growth hormone secretion, ranging from 20 to 66 ng/ml (peak values) and from 3619 to 8621 ng.min.ml-1 (areas under the curve). The insulin infusion rate selected for each patient was positively correlated with the nocturnal growth hormone secretion (area under the curve) (r = 0.87, p less than 0.01). On the other hand, there was no relationship between the nocturnal growth hormone secretion and the magnitude of the early morning blood glucose rise (r = -0.48, p greater than 0.2). We conclude that, in Type 1 (insulin-dependent) diabetic adolescents, the dawn phenomenon exists but is moderate despite important growth hormone surges; the nocturnal growth hormone secretion influences the nocturnal insulin requirements but not the dawn phenomenon itself, if insulinisation is adequate.
Article
The frequency of the dawn phenomenon has been studied in non-insulin-dependent diabetic (NIDDM) patients while they continued with their conventional therapy. Plasma glucose (PG) and immunoreactive insulin (IRI) were estimated hourly from 0300 to 0900 h in 19 NIDDM patients; 9 patients were treated by diet alone (group 1), and 10 patients were treated by diet and oral hypoglycemic agents (group 2). The dawn rise of plasma glucose was demonstrated in 17 (89.5%) of the 19 patients with mean +/- SE plasma glucose at 0300 h of 7.0 +/- 0.5 mM and at 0800 h of 8.4 +/- 0.6 (P less than .01). IRI in all patients rose from 14.7 +/- 1.3 microU/ml at 0500 h to 18.1 +/- 1.8 microU/ml at 0700 h (P less than .05). The changes in IRI levels at any time from 0300 to 0800 h in groups 1 and 2 when considered separately were insignificant. Thus, the dawn phenomenon occurs commonly in NIDDM patients taking their conventional therapy.
Article
To test the hypothesis that nocturnal hypoglycemia causes fasting hyperglycemia (the Somogyi phenomenon) in patients with insulin-dependent diabetes mellitus, we studied 10 patients, who were on their usual therapeutic regimens, from 10 p.m. through 8 a.m. on three nights. On the first night, only a control procedure was performed (blood sampling only); on the second night, hypoglycemia was prevented (by intravenous glucose infusion, if necessary, to keep plasma glucose levels above 100 mg per deciliter [5.6 mmol per liter]); and on the third night, hypoglycemia was induced (by stepped intravenous insulin infusions between midnight and 4 a.m. to keep plasma glucose levels below 50 mg per deciliter [2.8 mmol per liter]). After nocturnal hypoglycemia was induced (36 +/- 2 mg per deciliter [2.0 +/- 0.1 mmol per liter] [mean +/- SE] from 2 to 4:30 a.m.), 8 a.m. plasma glucose concentrations (113 +/- 18 mg per deciliter [6.3 +/- 1.0 mmol per liter]) were not higher than values obtained after hypoglycemia was prevented (182 +/- 14 mg per deciliter [10.1 +/- 0.8 mmol per liter]) or those obtained after blood sampling only (149 +/- 20 mg per deciliter [8.3 +/- 1.1 mmol per liter]). Indeed, regression analysis of data obtained on the control night indicated that the 8 a.m. plasma glucose concentration was directly related to the nocturnal glucose nadir (r = 0.761, P = 0.011). None of the patients was awakened by hypoglycemia. Scores for symptoms of hypoglycemia, which were determined at 8 a.m., did not differ significantly among the three studies. We conclude that asymptomatic nocturnal hypoglycemia does not appear to cause clinically important fasting hyperglycemia in patients with insulin-dependent diabetes mellitus on their usual therapeutic regimens.
Article
In order to assess whether the metabolic clearance of insulin changes overnight, 11 patients with Type 1 (insulin-dependent) diabetes and low insulin antibody titre, and 6 nondiabetic subjects were studied. In these studies insulin was always infused by a Harvard pump. Initially, the nocturnal insulin requirements were assessed in the diabetic patients by an overnight feedback insulin infusion to maintain euglycaemia. The insulin requirements decreased continuously after midnight to a nadir of 0.115 +/- 0.014 mU X kg-1 X min-1 at 04.30 hours, but after 05.00 hours the insulin requirements increased nearly 40 percent to a maximum of 0.16 +/- 0.012 mU X kg-1 X min-1 at 07.00 hours. To assess whether plasma insulin clearance changes overnight, the diabetic patients were studied on two different occasions, from 22.00-02.30 hours and from 04.00-08.30 hours. During each of these two studies insulin was infused in sequential steps of 90 min each at the rate of 0.13, 0.40 and 0.20 mU X kg-1 X min-1. Despite changes in plasma free insulin concentration, the metabolic clearance of insulin in the interval 22.00-02.30 hours (12.6 +/- 0.17 ml X kg-1 X min-1) was no different from that of the interval 04.00-08.30 hours (12.5 +/- 0.19 ml X kg-1 X min-1). The nondiabetic subjects were studied on two different occasions to assess whether the metabolic clearance of insulin changes overnight. Somatostatin (0.25 mg/h) and insulin (0.3 mU X kg-1 X min-1) were infused from 22.00-02.30 hours on one occasion, and from 04.00-08.30 hours on the other.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
A fall in plasma IRI despite constant C-peptide levels during prolonged insulin euglycemic clamp studies using the Biostator (Ames Division, Miles Laboratories, Elkhart, Indiana) prompted a meticulous evaluation of the Biostator's insulin delivery system. At slow infusion rates, a striking loss of immunoreactive and biologically active insulin was observed after 6 h of the Biostator run. Studies with labeled insulin indicated that the loss of insulin was not due to adsorption of insulin to the tubing since recovery of labeled insulin was close to 100%. A variety of techniques (gel filtration, polyacrylamide gel electrophoresis, centrifugation, and Coomassie Brilliant Blue protein assay) indicated that the loss of insulin activity was due to insulin coming out of solution. The insoluble nature of the immunologically and biologically inactive insulin was confirmed by centrifugation, i.e., 88% 125I-insulin precipitated into the pellet. The dependency of this loss of insulin activity on flow rate was clearly demonstrable with activity (IRI) less than 20% of expected at flow rates of 2.1 ml/h, and 30% at 4.2 ml/h. Full recovery was observed only with flow rates of 16.8 ml/h or greater. At each flow rate, IRI rose only after delivery of the effluent between the pump and exit port, demonstrating that insulin alteration occurs within the pump assembly presumably from heat-induced aggregation. Investigators employing the Biostator should carefully examine their systems for this time- and flow rate-dependent alteration of insulin. The loss of IRI at low flow rates (low-dose insulin clamp or insulin delivery during basal periods) will profoundly influence data generated from the Biostator.
Article
During constant insulin infusion (0.15 mU X kg-1 X min-1) from 12 PM to 8 AM in 10 IDDM patients previously rendered euglycemic (Biostator), plasma glucose (5.4 +/- 0.2 mmol/L at 12 PM) increased by 3:30 AM and reached 12.1 +/- 1.6 mmol/L at 8 AM (P less than 0.001). Glucose production also increased at 3:30 AM; hyperglycemia, glucose utilization did not increase until after 5 AM. Plasma growth hormone (12 PM to 4 AM), cortisol (after 3:30 AM), noradrenaline (after 1:30 AM), and adrenaline (after 3:30 AM) but not glucagon increased significantly overnight, although plasma adrenaline and noradrenaline remained at subthreshold levels. Insulin clearance increased (approximately 25%, P less than 0.05) but only after 7 AM, resulting in a 4 mU/L decrease in plasma insulin. A significant correlation was found between increases in plasma glucose and increases in glucose production (r = 0.74, P less than 0.05) which in turn were significantly correlated with nocturnal peaks in plasma growth hormone (r = 0.66, P less than 0.05). From the sequence of events observed, we conclude that the Dawn Phenomenon in IDDM begins earlier than is currently thought (approximately 3:30 AM), that it is due to both accelerated glucose production and impaired glucose utilization, and that nocturnal increases in sympathetic nervous system activity and/or growth hormone secretion, but not changes in secretion of cortisol, adrenaline and glucagon or changes in insulin clearance, may be of pathogenetic importance.
Article
We assessed the quality of overnight glycemic control and the frequency of the "dawn phenomenon" (nadir-0800 h glycemic increase) in 41 insulin-dependent diabetic patients treated by continuous subcutaneous insulin infusion (CSII). Mean plasma glucose levels were near-normal during the 24 h and, in particular, constant throughout the night. In a subset of six patients overnight plasma free insulin concentrations were also constant during CSII. The majority of profiles (88%) showed a glucose nadir from 2.0 to 5.9 mmol/L (most frequently at 0600 h) and had an 0800 h value from 2.0 to 6.9 mmol/L (92%). A large proportion (46%) of profiles showed a zero or negative nadir-0800 h glycemic increase. In 22 patients with three or more profiles recorded at the same basal insulin infusion rate, only one of 103 profiles had a fasting glycemic increase greater than an arbitrary value of 5.0 mmol/L (5.3), although many patients exhibited small dawn glycemic increases (e.g., 14 of 22 had a mean increase of from 0 to 2 mmol/L). In 12 subjects a 15% reduction in basal insulin infusion rate increased the mean +/- SEM dawn glycemic increase from 0.58 +/- 0.25 mmol/L to 2.7 +/- 0.76 mmol/L (P less than 0.025) as well as significantly increasing the nocturnal nadir and 0800 h plasma glucose concentrations. Thus, a marked dawn phenomenon is rare when a single but adequate basal infusion rate is used for CSII, and this questions the need in the majority of patients for preprogrammable pumps with nocturnal infusion rate changes.