The role of leptin in the regulation of carbohydrate metabolism

The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described as acting on the satiety centre in the hypothalamus through specific receptors (ob-R) to restrict food intake and enhance energy expenditure. Leptin plays a crucial role in the maintenance of body weight and glucose homeostasis hrough central and peripheral pathways, including regulation of insulin secretion by pancreatic b cells. Leptin may also directly affect the metabolism and function of peripheral tissues. Leptin has been implicated in causing peripheral insulin resistance by attenuating insulin action, and perhaps insulin signalling, in various insulin-responsive cell types. Research has demonstrated a significant relationship between leptin and insulin, but the mechanisms underlying the changes of leptin induced by insulin, and vice versa, remain to be studied in more detail. Recent data provides convincing evidence that leptin has beneficial effects on glucose homeostasis in mouse models of insulin-deficient type 1 diabetes mellitus. Our study suggests that leptin could be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic properties of leptin as an anti-diabetic agent. Safety evaluation should include a careful assessment of the effects of this combination therapy on the counterregulatory response to hypoglycaemia. The role of leptin in alpha-cell function has not been studied in detail. Extensive studies will be needed to determine the long-term safety and efficacy of this therapy.     

Serum insulin-like growth factor-I levels and potential risk of type 2 diabetes

The effects of circulating insulin-like growth factor (IGF)-I on increasing insulin sensitivity are well recognized. IGF-I may have a further important role in maintaining beta-cell mass, and lower IGF-I activity could explain links between small size at birth and risk of type 2 diabetes in short, obese adults. In the representative Avon Longitudinal Study of Pregnancy and Childhood birth cohort, whereas insulin sensitivity is related to early postnatal weight gain, insulin secretion is related to IGF-I level and statural growth. Adult studies suggest that lower IGF-I levels at baseline predict increased risk for developing impaired glucose tolerance and type 2 diabetes. A common genetic polymorphism in the IGF1 gene could influence size at birth, postnatal growth and type 2 diabetes risk, but results of studies have been inconsistent. Extrapolation of these data to short children born small for gestational age is complex. Some have evidence of IGF-I and insulin resistance, suggesting inherent defects in IGF-I signalling. These children have poor growth responses to growth hormone (GH) therapy and perhaps the highest type 2 diabetes risk. Where these metabolic abnormalities are less severe, responses to GH therapy are good and diabetes risk may then depend on other genetic factors, indicated by a family history of diabetes or origin from ethnic groups with high diabetes prevalence.     

Natural course of preclinical type 1 diabetes

The clinical presentation of type 1 diabetes is preceded by an asymptomatic latent period characterized by the presence of diabetes-associated autoantibodies in the peripheral circulation, reflecting beta-cell damage. This prediabetic period may last for months and years. Several studies observing genetically susceptible subjects from birth have shown that insulin autoantibodies (IAA) are the first or among the first autoantibodies to appear in young children, implying that insulin may be the primary autoantigen in most cases of childhood type 1 diabetes. About 12-16% of siblings of children with type 1 diabetes have been observed to test positive for at least one diabetes-associated autoantibody, whereas the risk of diabetes among siblings has been estimated to be 6-8%. In parallel, close to 4% of Finnish schoolchildren tested positive for at least one diabetes-associated autoantibody; the lifetime risk of type 1 diabetes in the Finnish population has been estimated to be close to 1%. These observations suggest that only 25-50% of those with signs of beta-cell autoimmunity eventually progress to clinical type 1 diabetes. Accordingly there is a considerable proportion of children in whom beta-cell autoimmunity remains subclinical or is aborted. Positivity for only one diabetes-associated autoantibody may actually represent innocent beta-cell autoimmunity, while positivity for two or more autoantibodies seems to mark a point of no return. The autoimmune response is very dynamic in the early phase of prediabetes, with spreading from one antigen to another and from one epitope to another within a given antigen. In addition both isotype spreading and switching can be observed in early prediabetes. This indicates that the early prediabetic process may be a suitable target for immunomodulation aimed at delaying or preventing progression to clinical diabetes.     

Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin.

The prevalence of nocturnal biochemical hypoglycaemia--that is, blood glucose concentrations below 3 mmol/l (55 mg/100 ml)--was evaluated in a random sample of 58 insulin dependent diabetics receiving twice daily insulin. Seventeen patients had at least one blood glucose value below 3 mmol/l (55 mg/100 ml) and five a value below 2 mmol/l (36 mg/100 ml) during the night. Both bedtime (2300) and fasting morning (0700) blood glucose concentrations were significantly lower in the group with nocturnal hypoglycaemia compared with the group without (p less than 0.00001). If the bedtime blood glucose concentration was below 6 mmol/l (108 mg/100 ml) the risk of nocturnal hypoglycaemia was 80% (95% confidence limits 51-96%). If the bedtime blood glucose concentration was above 6 mmol/l the likelihood of hypoglycaemia not occurring during the night was 88% (74-96%). The mean glycosylated haemoglobin A1c (HbA1c) concentration in the group with nocturnal biochemical hypoglycaemia (8.2 (range 5.0-12.4)%) was significantly lower than that in the group without (9.4(7.0-14.2)%) (p less than 0.02). The prevalence of nocturnal hypoglycaemia in the patients receiving twice daily insulin (29%) was compared with that in 15 patients receiving thrice daily insulin (47%) and was not found to be significantly different. The likelihood of this risk being greater with thrice daily insulin was, however, 88%. No patient with nocturnal biochemical hypoglycaemia woke up during the night with symptomatic hypoglycaemia. Nocturnal biochemical hypoglycaemia is common during twice daily treatment with insulin, and low values of HbA1c might be associated with a higher risk of such hypoglycaemia. The blood glucose concentration at bedtime is a significant predictor of nocturnal biochemical hypoglycaemia, and HbA1c values might be of help in identifying patients at risk.     

Effect of prior hyperglycemia on IL-6 responses to exercise in children with type 1 diabetes

The proinflammatory cytokine interleukin-6 (IL-6) may modulate the onset and progression of complications of diabetes. As this cytokine increases after exercise, and many other exercise responses are altered by prior glycemic fluctuations, we hypothesized that prior hyperglycemia might exacerbate the IL-6 response to exercise. Twenty children with type 1 diabetes (12 boys/8 girls, age 12-15 yr) performed 29 exercise studies (30-min intermittent cycling at approximately 80% peak O2 uptake). Children were divided into four groups based on highest morning glycemic reading [blood glucose (BG) < 150, BG 151-200, BG 201-300, or BG > 300 mg/dl]. All exercise studies were performed in the late morning, after hyperglycemia had been corrected and steady-state conditions (plasma glucose < 120 mg/dl, basal insulin infusion) had been maintained for > or = 90 min. Blood samples for IL-6, growth factors, and counterregulatory hormones were drawn at pre-, end-, and 30 min postexercise time points. At all time points, circulating IL-6 was lowest in BG < 150 and progressively higher in the other three groups. The exercise-induced increment also followed a similar dose-response pattern (BG < 150, 0.6 +/- 0.2 ng/ml; BG 151-200, 1.2 +/- 0.8 ng/ml; BG 201-300, 2.1 +/- 1.1 ng/ml; BG > 300, 3.2 +/- 1.4 ng/ml). Other measured variables (growth hormone, IGF-I, glucagon, epinephrine, cortisol) were not influenced by prior hyperglycemia. Recent prior hyperglycemia markedly influenced baseline and exercise-induced levels of IL-6 in a group of peripubertal children with type 1 diabetes. While exercise is widely encouraged and indeed often considered part of diabetic management, our data underscore the necessity to completely understand all adaptive mechanisms associated with physical activity, particularly in the context of the developing diabetic child.     

Diagnosis of the metabolic syndrome in children

PURPOSE OF REVIEW: The metabolic syndrome, a cluster of potent risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus in adults, is composed of insulin resistance, obesity, hypertension and hyperlipidemia. Of significant impact in the adult population, atherosclerotic cardiovascular disease and death are rarely seen in the young, but the pathologic processes and risk factors associated with its development have been shown to begin during childhood. The current review summarizes the work published during the past year in the following areas: childhood obesity, insulin resistance, dyslipidemia, hypertension and type 2 diabetes mellitus. RECENT FINDINGS: Recent studies have revealed the presence of components of the metabolic syndrome in children and adolescents. Obesity has a central role in the syndrome. There is an increasing amount of data to show that being overweight during childhood and adolescence is significantly associated with insulin resistance, abnormal lipids, and elevated blood pressure in young adulthood. Weight loss in these situations results in a decrease in insulin concentration and an increase in insulin sensitivity toward normalcy. With cardiovascular disease, obesity, and type 2 diabetes reaching epidemic proportions, it is of great importance to understand and control the risk factors at an early age. SUMMARY: The information obtained during the past year has improved our understanding of the pathogenesis, diagnosis and treatment of components of the metabolic syndrome in children, and potentially could improve the risk profiles for cardiovascular disease as children make the transition toward adolescence and young adulthood.     

Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawareness after transferring to human insulin.

OBJECTIVES--To compare awareness of hypoglycaemia and physiological responses to hypoglycaemia with human and porcine insulin in diabetic patients who reported loss of hypoglycaemia awareness after transferring to human insulin. DESIGN--Double blind randomised crossover study of clinical experience and physiological responses during slow fall hypoglycaemic clamping with porcine and human insulin. SETTING--Clinical investigation unit of teaching hospital recruiting from diabetes clinics of five teaching hospitals and one district general hospital. SUBJECTS--17 patients with insulin dependent diabetes mellitus of more than five years'' duration who had reported altered hypoglycaemia awareness within three months of transferring to human insulin. MAIN OUTCOME MEASURES--Glycaemic control and frequency of hypoglycaemic episodes during two months'' treatment with each insulin. Glucose thresholds for physiological and symptomatic responses during clamping. RESULTS--Glycaemic control did not change with either insulin. 136 hypoglycaemic episodes (eight severe) were reported with human insulin and 149 (nine severe) with porcine insulin (95% confidence interval -4 to 2.5, p = 0.63). 20 episodes of biochemical hypoglycaemia occurred with human insulin versus 18 with porcine insulin (-0.8 to 1, p = 0.78). During controlled hypoglycaemia the mean adrenaline response was 138 nmol/l/240 min for both insulins; neurohormonal responses were triggered at 3.0 (SE 0.2) versus 3.1 (0.2) mmol/l of glucose for adrenaline and 2.5 (0.1) versus 2.5 (0.1) mmol/l for subjective awareness. CONCLUSIONS--These data suggest that human insulin per se does not affect the presentation of hypoglycaemia or the neurohumoral, symptomatic, and cognitive function responses to hypoglycaemia in insulin dependent diabetic patients with a history of hypoglycaemia unawareness.     

Growth hormone responses to sleep, insulin hypoglycaemia and arginine infusion

This study compares the peak serum growth hormone (GH) concentration during slow wave sleep with the serum GH responses to insulin-induced hypoglycaemia and intravenous arginine infusion in 23 children referred because of short stature (20) or precocious puberty (3). Peak serum GH concentration during sleep correlated significantly with peak GH response to insulin hypoglycaemia (r = 0.64, p less than 0.01) and arginine infusion (r = 0.57, p less than 0.01). 3 children had subnormal (less than 15 mU/l) peak serum GH concentrations during sleep but normal responses to either insulin-induced hypoglycaemia or intravenous arginine infusion. 1 child had a normal peak serum GH response to sleep but subnormal responses to insulin and arginine. Sleep studies of GH secretion may be indicated when the GH responses to pharmacological stimuli are inconsistent with the observed growth pattern.     

Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin: a case control study.

OBJECTIVE--To examine whether transfer from animal insulin to human insulin is associated with an increased risk of severe hypoglycaemia. DESIGN--Matched case-control study of insulin treated diabetic patients admitted to hospital because of hypoglycaemia during 1984-7, the period when human insulin was introduced into treatment. SETTING--Case admissions and control admissions were obtained from eight public hospitals within the Swiss canton of Berne and a second control group comprised members of the Bernese section of the Swiss Diabetes Association. SUBJECTS--94 patients with insulin treated diabetes with a total of 112 admissions for hypoglycaemia during 1984-7 (case admissions), 182 patients with insulin treated diabetes seen in the same hospitals for reasons other than hypoglycaemia with a total of 225 admissions (control admissions), and 86 insulin treated diabetic patients who were members of the Bernese section of the Swiss Diabetes Association. MAIN OUTCOME MEASURES--Type of insulin used at time of admission, glycaemic control as measured by amount of glycated haemoglobin or glucose concentration; severity of hypoglycaemia. RESULTS--Treatment with human insulin at admission was more common in cases than controls (52/112 (46%) admissions v 77/225 (34%); p = 0.003). 116 out of 129 (90%) of admissions taking human insulin had been transferred from animal insulin, mainly because of non-availability of porcine insulins. The ratio of rate of hypoglycaemia in those taking human insulin to the rate in those taking animal insulin was 2.4 (95% confidence interval 1.3 to 4.4). Other risk factors for hypoglycaemia were a history of hypoglycaemic coma (rate ratio of history to no history 3.8, 2.3 to 6.4) and good glycaemic control (rate ratio of good to poor control 3.9, 1.4 to 7.5). With multivariate analysis the increase in rate ratio associated with use of human insulin rose to 3.0 (1.4 to 6.4). Comparison with the diabetes association controls also showed an increased risk associated with use of human insulin (2.2; 1.1 to 4.8). CONCLUSIONS--Transfer of treatment from animal insulin to human insulin was associated with an increased risk of severe hypoglycaemia. Caution should be exercised when transferring diabetic patients to human insulin. Further studies are required to elucidate why this effect occurs.     

Selection for and initiation of continuous subcutaneous insulin infusion. Proceedings from a workshop

Continuous subcutaneous insulin infusion (CSII) has been used in the paediatric age group for more than 20 years. The technique is not yet widely used in most countries but there has recently been increasing interest in pump therapy for young children and adolescents. In 1999, 7.5% of Swedish children and adolescents with diabetes used pumps, now the figure is approaching 12%. The indication for starting pump therapy has usually been a medical problem, but today quality of life issues are becoming increasingly important. One technique sometimes used is to start CSII by wearing the pump only at night. Daily insulin requirements are usually decreased compared with injection therapy. Studies have shown that it is possible to lower HbA1c when using an insulin pump and that the risk of severe hypoglycaemia can be lowered. The use of CSII has also been successful in preventing recurrent admission for diabetic ketoacidosis. While starting pump therapy does take an extra effort from both the diabetes team and the family, routine visits are generally no more time-consuming than for patients on multiple injection therapy. CSII can be initiated during admission to hospital but most pumps are started on an outpatient basis. Our department has the patients on the day care ward for 3-4 days of 'pump school'. Parents wear a saline pump for practice. The total daily insulin dose is usually lowered 15-20% compared with multiple injections; on average 40-50% (sometimes up to 60%) of the daily dose is given as basal rate. We start all pumps on rapid-acting analogues and use 40 IU/ml if the basal rate is <0.3 IU/h. In conclusion, the use of CSII in children and adolescents is well accepted and can be managed safely.     

Effect of sex on counterregulatory responses to exercise after antecedent hypoglycemia in type 1 diabetes

A marked sexual dimorphism exists in healthy individuals in the pattern of blunted neuroendocrine and metabolic responses following antecedent stress. It is unknown whether significant sex-related counterregulatory differences occur during prolonged moderate exercise after antecedent hypoglycemia in type 1 diabetes mellitus (T1DM). Fourteen patients with T1DM (7 women and 7 men) were studied during 90 min of euglycemic exercise at 50% maximal O(2) consumption after two 2-h episodes of previous-day euglycemia (5.0 mmol/l) or hypoglycemia of 2.9 mmol/l. Men and women were matched for age, glycemic control, duration of diabetes, and exercise fitness and had no history or evidence of autonomic neuropathy. Exercise was performed during constant "basal" intravenous infusion of regular insulin (1 U/h) and a 20% dextrose infusion, as needed to maintain euglycemia. Plasma glucose and insulin levels were equivalent in men and women during all exercise and glucose clamp studies. Antecedent hypoglycemia produced a relatively greater (P < 0.05) reduction of glucagon, epinephrine, norepinephrine, growth hormone, and metabolic (glucose kinetics) responses in men compared with women during next-day exercise. After antecedent hypoglycemia, endogenous glucose production (EGP) was significantly reduced in men only, paralleling a reduction in the glucagon-to-insulin ratio and catecholamine responses. In conclusion, a marked sexual dimorphism exists in a wide spectrum of blunted counterregulatory responses to exercise in T1DM after prior hypoglycemia. Key neuroendocrine (glucagon, catecholamines) and metabolic (EGP) homeostatic responses were better preserved during exercise in T1DM women after antecedent hypoglycemia. Preserved counterregulatory responses during exercise in T1DM women may confer greater protection against hypoglycemia than in men with T1DM.     

A one-year, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes.

AIMS: The aim of the trial was to compare the efficacy and safety of the new, long-acting basal insulin, insulin glargine (LANTUS(R)), with NPH human insulin, each administered in a combination regimen with oral antidiabetic drugs in patients with Type 2 diabetes. METHODS: In a multicentre, open, randomised study, 570 patients with Type 2 diabetes, aged 34 - 80 years, were treated for 52 weeks with insulin glargine or NPH insulin given once daily at bedtime. Previous oral antidiabetic therapy was continued throughout the study. RESULTS: There was a clinically relevant decrease in glycosylated haemoglobin (GHb) values from baseline to endpoint with both drugs (insulin glargine: - 0.46 %; NPH insulin: - 0.38 %; p = 0.415); also, this difference was statistically significant in the subgroup of overweight patients with BMI > 28 kg/m 2 (insulin glargine: - 0.42 %, NPH insulin: - 0.11 %; p = 0.0237). Over the entire treatment period, NPH insulin-treated patients (41 %) and insulin glargine-treated patients (35 %) experienced a similar level of symptomatic hypoglycaemia. A statistically significant difference was observed in the number of patients treated with NPH insulin who reported at least one episode of nocturnal hypoglycaemia compared with those treated with insulin glargine in the overall population and in the overweight subgroup (overall: 24 % vs. 12 %, p = 0.002; overweight: 22.2 % vs. 9.5 %, p = 0.0006), using the Cochran-Mantel-Haenszel test. These differences were most pronounced in insulin-na?ve and overweight (BMI > 28 kg/m 2) sub-groups. The incidence of adverse events was similar for the two treatments. CONCLUSIONS: This study demonstrated that insulin glargine is as effective as NPH insulin in achieving glycaemic control in patients with Type 2 diabetes, and is associated with fewer episodes of symptomatic hypoglycaemia, particularly nocturnal episodes.     

Babies born small for gestational age: insulin sensitivity and growth hormone treatment

Epidemiological studies have identified an association between size at birth and adult risk for type 2 diabetes mellitus and cardiovascular disease. In contemporary populations, children who are relatively small at birth and show rapid infancy weight gain are at greatest risk for the development of childhood obesity, increased visceral fat and insulin resistance: possible early markers of adult disease risk. Individuals presenting to growth clinics with short stature and a history of low birthweight will not have shown post-natal catch-up growth and may be a very heterogeneous group. Nevertheless, there are some data to suggest that as a group they are insulin resistant with decreased lean mass. Growth hormone treatment leads to reversible worsening of the insulin resistance, and short-term data do not indicate an increased risk for type 2 diabetes. However, further long-term follow-up is required, and particular care should be taken in monitoring children with a strong family history of type 2 diabetes and those from ethnic groups in which there is a high background prevalence of the disease.     

Effect of differing antecedent hypoglycemia on counterregulatory responses to exercise in type 1 diabetes

Hypoglycemia frequently occurs during or after exercise in intensively treated patients with type 1 diabetes mellitus (T1DM), but the underlying mechanisms are not clear. In both diabetic and nondiabetic subjects, moderate hypoglycemia blunts counterregulatory responses to subsequent exercise, but it is unknown whether milder levels of hypoglycemia can exert similar effects in a dose-dependent fashion. This study was designed to test the hypothesis that prior hypoglycemia of differing depths induces acute counterregulatory failure of proportionally greater magnitude during subsequent exercise in T1DM. Twenty-two T1DM patients (11 males/11 females, HbA1c 8.0 +/- 0.3%) were studied during 90 min of euglycemic cycling exercise after two 2-h periods of previous day euglycemia or hypoglycemia of 3.9, 3.3, or 2.8 mmol/l (HYPO-3.9, HYPO-3.3, HYPO-2.8, respectively). Patients' counterregulatory responses (circulating levels of neuroendocrine hormones, intermediary metabolites, substrate flux, tracer-determined glucose kinetics, and cardiovascular measurements) were assessed during exercise. Identical euglycemia and basal insulin levels were successfully maintained during all exercise studies, regardless of blood glucose levels during the previous day. After day 1 euglycemia, patients displayed normal counterregulatory responses to exercise. Conversely, when identical exercise was performed after day 1 hypoglycemia of increasing depth, a progressively greater blunting of glucagon, catecholamine, cortisol, endogenous glucose production, and lipolytic responses to exercise was observed. This was paralleled by a graduated increase in the amount of exogenous glucose needed to maintain euglycemia during exercise. Our results demonstrate that acute counterregulatory failure during prolonged, moderate-intensity exercise may be induced in a dose-dependent fashion by differing depths of antecedent hypoglycemia starting at only 3.9 mmol/l in patients with T1DM.     

Effect of a long-acting somatostatin derivative SMS 201-995 (sandostatin) on glucose homeostasis in type I diabetes mellitus

The infusion of natural somatostatin (SRIF) has been able to partially correct postprandial hyperglycemic reactions in insulin-dependent diabetes mellitus (IDDM). SMS 201-995 (Sandostatin) is a long-acting derivative with a growth hormone-suppressive effect 10-60 times more potent than the native peptide. The effect of SMS 201-995 (50 micrograms s.c.) on glucose control by exogenous insulin has been documented in a series of type I diabetics after stabilization of blood sugar by an artificial pancreas. Inhibition of counterregulatory mechanisms significantly diminished the postprandial hyperglycemia, and insulin requirements, both total and 2 h after meals, were markedly decreased. Also the effect of a single s.c. injection of 100 micrograms SMS 201-995 on the dawn phenomenon in a patient with poorly adjustable diabetes was investigated. The glucose escape observed during the control night was blocked by SMS 201-995. Thus, the stabilizing action of this peptide on postprandial and nocturnal hyperglycemia in unstable diabetes warrants further studies.     

Growth and body composition in type 1 diabetes mellitus

Over the last 50 years the prognosis for growth and pubertal development in children with type 1 diabetes mellitus (T1DM) has improved considerably. The early reports of Mauriac's syndrome were related not only to relative deficiency of insulin but also reduced caloric intake. Improved insulin delivery and liberalisation of caloric intake has resulted in improved growth, but subtle abnormalities persist. The frequently reported increased height at diagnosis may relate to prior hyperinsulinaemia and genetic background with respect to lDDM2 the insulin gene VNTR. Subsequent growth faltering is thought to be related to impairment of the GH/IGF-1 axis but children with T1DM are also more at risk of hypothyroidism and coeliac disease. At puberty, persisting abnormalities of the GH/IGF-1 axis and our inability to reverse these totally, even with intensified insulin therapy, contribute to the blunted pubertal growth in the girls but abnormal sex steroid concentrations may also be important. Intensification of insulin therapy may result in leptin resistance and excessive gains in fat mass, particularly in girls. Although it is likely that most children with T1DM will have normal final heights, this excessive weight gain in girls may lead to problems with compliance. Furthermore, hyperinsulinaemia in these subjects may also lead to ovarian hyperandrogenism, increased early risk of microvascular complications and long-term risk of cardiovascular disease.     

Glycaemic effects of incretins in Type 1 diabetes mellitus: a concise review, with emphasis on studies in humans

The remission phase of Type 1 diabetes mellitus is associated with substantial recovery of beta-cell function and with marked improvement of endogenous insulin responses to meals in the early months after diagnosis, accompanied by little or no improvement in the insulin response to parenteral glucose, suggesting that the incretin function may be important in glycaemic regulation in this phase of diabetes. Preservation of the insulin response to parenteral glucagon-like peptide-1 (GLP-1), contrasting with lack of stimulation of insulin secretion by the other known incretin gastric inhibitory polypeptide (GIP), prompted studies with exogenous GLP-1 in recent-onset Type 1 diabetes. These studies showed substantial reduction of glycaemic excursions after ingestion of mixed nutrients during intravenous infusion of GLP-1 without administration of insulin, in subjects with a range of endogenous secretion of insulin in response to meals as demonstrated by blood levels of the insulin-connecting peptide (CP). These effects were independent of stimulation of blood levels of CP and were reproduced in volunteers with no endogenous release of CP in response to meals. The glycaemic effects were associated with inhibition of abnormal rises of blood levels of glucagon, and with suppression of endogenous release of human pancreatic polypeptide (HPP), by GLP-1. It was hypothesized that a major component of the glycaemic effect is attributable to the known action of GLP-1 to inhibit gastric emptying and to inhibit glucagon secretion. Studies of the effects of GLP-1 agonists (GLP-1 and exendin-4) given together with established insulin doses before a meal supported the hypothesis. The more prolonged actions of exendin-4 were accompanied by greater and more prolonged reduction of glycaemic effects of ingestion of meals in volunteers with CP-negative Type 1 diabetes mellitus, during intensive insulin therapy, in whom delay of gastric emptying was confirmed by studies of blood levels of acetaminophen ingested with the meals. Side effect-free doses of exendin-4 given together with insulin in volunteers with CP-negative Type 1 diabetes receiving continuing intensive insulin therapy demonstrated the capacity of this combination therapy to normalize blood glucose levels after ingestion of meals that were consistent with the dietary program of the volunteers, without apparent increased risk of hypoglycaemia within a normal between-meals interval. It is suggested that further and more prolonged studies of the use of long-acting GLP-1 agonists as congeners with insulin in Type 1 diabetes mellitus are indicated.     

Pituitary Polypeptide with Hypoglycaemic Action in Diabetes Mellitus

A polypeptide isolated by the hydrolysis of growth hormone, studied in five patients with diabetes mellitus, has been shown able to produce hypoglycaemia, presumably by modifying the anti-insulin action of pituitary growth hormone. Possibly this substance may be suitable for treating cases of insulin resistance or when a circulating inhibitor of glucose uptake is present.     

Prevalence and Incidence of Hypoglycaemia in 532,542 People with Type 2 Diabetes on Oral Therapies and Insulin: A Systematic Review and Meta-Analysis of Population Based Studies

Objective

To collate and evaluate the current literature reporting the prevalence and incidence of hypoglycaemia in population based studies of type 2 diabetes.

Research Design and Methods

Medline, Embase and Cochrane were searched up to February 2014 to identify population based studies reporting the proportion of people with type 2 diabetes experiencing hypoglycaemia or rate of events experienced. Two reviewers independently screened studies for eligibility and extracted data for included studies. Random effects meta-analyses were carried out to calculate the prevalence and incidence of hypoglycaemia.

Results

46 studies (n = 532,542) met the inclusion criteria. Prevalence of hypoglycaemia was 45% (95%CI 0.34,0.57) for mild/moderate and 6% (95%CI, 0.05,0.07) for severe. Incidence of hypoglycaemic episodes per person-year for mild/moderate and for severe was 19 (95%CI 0.00, 51.08) and 0.80 (95%CI 0.00,2.15), respectively. Hypoglycaemia was prevalent amongst those on insulin; for mild/moderate episodes the prevalence was 50% and incidence 23 events per person-year, and for severe episodes the prevalence was 21% and incidence 1 event per person-year. For treatment regimes that included a sulphonylurea, mild/moderate prevalence was 30% and incidence 2 events per person-year, and severe prevalence was 5% and incidence 0.01 events per person-year. A similar prevalence of 5% was found for treatment regimes that did not include sulphonylureas.

Conclusions

Current evidence shows hypoglycaemia is considerably prevalent amongst people with type 2 diabetes, particularly for those on insulin, yet still fairly common for other treatment regimens. This highlights the subsequent need for educational interventions and individualisation of therapies to reduce the risk of hypoglycaemia.