Asimina Mitrakou

Role of Reduced Suppression of Glucose Production and Diminished Early Insulin Release in Impaired Glucose Tolerance

BACKGROUND Insulin resistance and impaired insulin secretion both occur in non-insulin-dependent diabetes (NIDDM), but their relative importance is unclear. Hyperglycemia itself has adverse effects on tissue insulin sensitivity and insulin secretion that make it difficult to distinguish between primary and secondary abnormalities. To avoid this problem we studied subjects with postprandial glucose intolerance but not sustained hyperglycemia. METHODS We compared the rate of systemic appearance and disappearance of glucose, the output of endogenous hepatic glucose, splanchnic and muscle uptake of glucose, and plasma insulin and glucagon responses after the ingestion of 1 g of glucose per kilogram of body weight in 15 subjects with impaired glucose tolerance (8 of them nonobese and 7 obese) and in 16 normal subjects (9 nonobese and 7 obese) who were matched for age and weight. RESULTS After glucose ingestion the mean (+/- SE) rate of total systemic appearance of glucose was significantly higher in both the nonobese subjects (455 +/- 12 mmol per five hours) and the obese subjects (486 +/- 17 mmol per five hours) with impaired glucose tolerance than in the respective normal subjects (411 +/- 11 and 436 +/- 7 mmol per five hours). This difference was fully accounted for by the reduced suppression of endogenous hepatic glucose in the subjects with impaired glucose tolerance (a reduction of about 28 percent, vs. 48 percent in the normal subjects; P less than 0.01). Despite late hyperinsulinemia, at 30 minutes the subjects with impaired glucose tolerance had smaller increases in plasma insulin and smaller reductions in plasma glucagon (both P less than 0.01). Molar ratios of plasma insulin to plasma glucagon levels correlated inversely (r = -0.62, P less than 0.001) with the rates of systemic glucose appearance; the latter correlated positively (r = 0.72, P less than 0.0001) with peak plasma glucose concentrations. CONCLUSIONS Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.

Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM.

To assess the role of muscle and liver in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), we administered an oral glucose load enriched with [14C]glucose to 10 NIDDM subjects and 10 age- and weight-matched nondiabetic volunteers and compared muscle glucose disposal by measuring forearm balance of glucose, lactate, alanine, O2, and CO2 (with forearm calorimetry). In addition, we used the dual-lable isotope method to compare overall rates of glucose appearance (Ra) and disappearance (Rd), suppression of endogenous glucose output, and splanchnic glucose sequestration. During the initial 1-1.5 h after glucose ingestion, plasma glucose increased by approximately 8 mM in NIDDM vs. approximately 3 mM in nondiabetic subjects (P less than 0.01); overall glucose Ra was nearly 11 g greater in NIDDM than nondiabetic subjects (45.1 +/- 2.3 vs. 34.4 +/- 1.5 g, P less than 0.01), but glucose Rd was not significantly different in NIDDM (35.1 +/- 2.4 g) and nondiabetic (33.3 +/- 2.7 g) subjects. The greater overall glucose Ra of NIDDM subjects was due to 6.8 g greater endogenous glucose output (13.7 +/- 1.1 vs. 6.8 +/- 1.0 g, P less than 0.01) and 3.8 g less oral glucose splanchnic sequestration of the oral load (31.4 +/- 1.5 vs. 27.5 +/- 0.9 g, P less than 0.05). Although glucose taken up by muscle was not significantly different in NIDDM and nondiabetic subjects (39.3 +/- 3.5 vs. 41.0 +/- 2.5 g/5 h), a greater amount of the glucose taken up by muscle in NIDDM was released as lactate and alanine (11.7 +/- 1.0 vs. 5.2 +/- 0.3 g in nondiabetic subjects, P less than 0.01), and less was stored (11.7 +/- 1.3 vs. 16.9 +/- 1.5 g, P less than 0.05). We conclude that increased systemic glucose delivery, due primarily to reduced suppression of endogenous hepatic glucose output and, to a lesser extent, reduced splanchnic glucose sequestration, is the predominant factor responsible for postprandial hyperglycemia in NIDDM.

Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population.

Patients with fatty liver (FL) disease have a high risk of developing diabetes and cardiovascular diseases. The aim was to evaluate the association between FL, insulin resistance (IR), coronary heart disease (CHD) risk, and early atherosclerosis in a large European population (RISC Study). In 1,307 nondiabetic subjects (age 30‐60 years) recruited at 19 centers, we evaluated liver enzymes, lipids, insulin sensitivity (by euglycemic‐hyperinsulinemic clamp), glucose tolerance (by 75 g oral glucose tolerance test), carotid atherosclerosis as intima media thickness (IMT), CHD risk by the Framingham Heart study prediction score, and physical activity (by accelerometer). The presence of FL was estimated using the fatty liver index (FLI; >60, likelihood >78% presence FL; FLI <20 likelihood >91% absence of FL). Subjects were divided into three groups: G1: FLI <20 (n = 608); G3: FLI >60 (n = 234), G2: intermediate group (n = 465). Compared to G1, G3 included more men (70% versus 24%) and people with impaired glucose tolerance (23% versus 5%). IMT increased with FLI (G3 = 0.64 ± 0.08 versus G1 = 0.58 ± 0.08 mm, P < 0.0001). FLI was associated with increased CHD risk (r = 0.48), low‐density lipoprotein cholesterol (r = 0.33), alanine aminotransferase (r = 0.48), aspartate aminotransferase (r = 0.25), systolic blood pressure (r = 0.39) and IMT (r = 0.30), and reduced insulin sensitivity (r = −0.43), high‐density lipoprotein cholesterol (r = −0.50), adiponectin (r = −0.42), and physical activity (r = −0.16, all P < 0.0001). The correlations hold also in multivariate analysis after adjusting for age, gender, and recruiting center. Conclusion: In middle‐age nondiabetic subjects, increased IMT, CHD risk, and reduced insulin sensitivity are associated with high values of FLI. (HEPATOLOGY 2009.)

Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus.

Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321+/-36 vs. 125+/-15 micromol/min, P < 0.001). Hepatic glucose release was increased approximately 30% (P = 0.03), but increments in hepatic and renal glucose release were comparable (2.60+/-0.70 vs. 2.21+/-0.32, micromol.kg-1.min-1, respectively, P = 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353+/-48 vs. 103+/-10 micromol/min, P < 0.001), resulting in net renal glucose uptake in the diabetic subjects (92+/-50 micromol/ min) versus a net output in the nondiabetic subjects (21+/-14 micromol/min, P = 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake (r = -0.51, P < 0.01), which was reduced by approximately 60% in diabetic subjects (10. 9+/-2.7 vs. 27.0+/-3.3 micromol/min, P < 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney.

Different Mechanisms for Impaired Fasting Glucose and Impaired Postprandial Glucose Tolerance in Humans

OBJECTIVE—To compare the pathophysiology of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a more comprehensive and standardized fashion than has hitherto been done. RESEARCH DESIGN AND METHODS—We studied 21 individuals with isolated IFG (IFG/normal glucose tolerance [NGT]), 61 individuals with isolated IGT (normal fasting glucose [NFG]/IGT), and 240 healthy control subjects (NFG/NGT) by hyperglycemic clamps to determine first- and second-phase insulin release and insulin sensitivity. Homeostasis model assessment (HOMA) indexes of β-cell function (HOMA-%B) and insulin resistance (HOMA-IR) were calculated from fasting plasma insulin and glucose concentrations. RESULTS—Compared with NFG/NGT, IFG/NGT had similar fasting insulin concentrations despite hyperglycemia; therefore, HOMA-IR was increased ∼30% (P < 0.05), but clamp-determined insulin sensitivity was normal (P > 0.8). HOMA-%B and first-phase insulin responses were reduced ∼35% (P < 0.002) and ∼30% (P < 0.02), respectively, but second-phase insulin responses were normal (P > 0.5). NFG/IGT had normal HOMA-IR but ∼15% decreased clamp-determined insulin sensitivity (P < 0.03). Furthermore, HOMA-%B was normal but both first-phase (P < 0.0003) and second-phase (P < 0.0001) insulin responses were reduced ∼30%. IFG/NGT differed from NFG/IGT by having ∼40% lower HOMA-%B (P < 0.012) and ∼50% greater second-phase insulin responses (P < 0.005). CONCLUSIONS—Since first-phase insulin responses were similarly reduced in IFG/NGT and NFG/IGT, we conclude that IFG is due to impaired basal insulin secretion and preferential resistance of glucose production to suppression by insulin, as reflected by fasting hyperglycemia despite normal plasma insulin concentrations and increased HOMA-IR, whereas IGT mainly results from reduced second-phase insulin release and peripheral insulin resistance, as reflected by reduced clamp-determined insulin sensitivity.

Renal glucose production and utilization: new aspects in humans

Summary According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although many animal and in vitro data have documented that the kidney is capable of gluconeogenesis, production of glucose by the human kidney in the postabsorptive state has generally been regarded as negligible. This traditional view is based on net balance measurements which, other than after a prolonged fast or during metabolic acidosis, showed no significant net renal glucose release. However, recent studies have refuted this view by combining isotopic and balance techniques, which have demonstrated that renal glucose production accounts for 25 % of systemic glucose production. Moreover, these studies indicate that glucose production by the human kidney is stimulated by epinephrine, inhibited by insulin and is excessive in diabetes mellitus. Since renal glucose release is largely, if not exclusively, due to gluconeogenesis, it is likely that the kidney is as important a gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactate, glutamine and glycerol. The implications of these recent findings on the understanding of the physiology and pathophysiology of human glucose metabolism are discussed. [Diabetologia (1997) 40: 749–757].

Induction of Hypoglycemia Unawareness by Asymptomatic Nocturnal Hypoglycemia

Hypoglycemia has been incriminated as a possible factor responsible for development of the hypoglycemia unawareness phenomenon in patients with type I diabetes. Many patients with this condition, however, do not have a history of recent hypoglycemia. Because asymptomatic nocturnal hypoglycemia commonly occurs in type I diabetes, we tested the hypothesis that such episodes might be capable of inducing this phenomenon. Accordingly, autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function were assessed during standardized insulin-induced hypoglycemia in 10 normal volunteer subjects on two occasions—once after induction of asymptomatic nocturnal hypoglycemia and once after control studies in which saline rather than insulin was infused overnight. Compared with control experiments, asymptomatic nocturnal hypoglycemia increased the threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction during subsequent hypoglycemia (all, P < 0.05). These results indicate that asymptomatic hypoglycemia may induce hypoglycemia unawareness and, thus, may explain why not every patient with this condition has a history of prior hypoglycemia. Our results therefore support the concept that in type I diabetes this phenomenon may be largely attributable to antecedent hypoglycemia.

Treatment modalities of obesity: what fits whom?

The prevalence of obesity is increasing in both developed and developing countries, with rates reaching ∼10–35% among adults in the Euro-American region. Obesity is associated with increased risks of cardiovascular diseases, type 2 diabetes, arthritis, and some type of cancers. Obesity significantly affects the quality of life and reduces the average life expectancy. The effective treatment of obesity should address both the medical and the social burden of this disease. Obesity needs to be treated within the health care system as any other complex disease, with empathy and without prejudice. Both health care providers and patients should know that the obesity treatment is a lifelong task. They should also set realistic goals before starting the treatment, whereas keeping in mind that even a modest weight loss of 5–15% significantly reduces obesity-related health risks. Essential treatment of obesity includes low-calorie low-fat diets, increased physical activity, and strategies contributing to the modification of lifestyle. Anti-obesity drugs facilitate weight loss and contribute to further amelioration of obesity-related health risks. A short-term weight loss, up to 6 months, is usually achieved easily. However, the long-term weight management is often associated with a lack of compliance, failures, and a high dropout rate. Regular physical activity, cognitive behavioral modification of lifestyle, and administration of anti-obesity drugs improve weight loss maintenance. Bariatric surgery is an effective strategy to treat severely obese patients. Bariatric surgery leads to a substantial improvement of comorbidities as well as to a reduction in overall mortality by 25–50% during the long-term follow-up. Obesity treatment should be individually tailored and the following factors should be taken into account: sex, the degree of obesity, individual health risks, psychobehavioral and metabolic characteristics, and the outcome of previous weight loss attempts. In the future, an evaluation of hormonal and genetic determinants of weight loss could also contribute to a better choice of individual therapy for a particular obese patient. A multilevel obesity management network of mutually collaborating facilities should be established to provide individually tailored treatment. Centers of excellence in obesity management represented by multidisciplinary teams should provide comprehensive programs for the treatment of obesity derived from evidence-based medicine.

Effect of Hyperketonemia and Hyperlacticacidemia on Symptoms, Cognitive Dysfunction, and Counterregulatory Hormone Responses During Hypoglycemia in Normal Humans

The brain usually depends almost exclusively on glucose for its energy requirements. During hypoglycemia associated with prolonged fasting or strenuous exercise, circulating ketone-body and lactate levels increase severalfold; in both situations, certain signs and symptoms of hypoglycemia are diminished. Therefore, to test the hypothesis that hyperketonemia or hyperlacticacidemia of the magnitude seen during certain clinical situations can substitute for glucose as an energy source for the brain and alter physiological responses to hypoglycemia, we assessed autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function during standardized insulin-induced hypoglycemia in normal volunteers with and without infusion of (β-hydroxybutyrate (BOHB) or lactate designed to reproduce circulating levels of these substrates seen during prolonged fasting and strenuous exercise. Compared with paired control experiments, infusion of BOHB and lactate increased the glycemic threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction (all P < 0.05). The hypoglycemic threshold for autonomic symptoms increased from 3.8 ± 0.1 to 3.1 ± 0.2 mmoM during BOHB infusion and from 3.7 ± 0.1 to 2.8 ± 0 . 1 mmol<1 during lactate infusion, and the threshold for neuroglycopenic symptoms increased from 2.8 ± 0.1 to 2.4 ± 0.1 and 2.3 ± 0.1 mmol/1, respectively. The magnitude for autonomic symptoms decreased from 12 ± 2 and 11 ± 1 to 6 ± 2 and 4 ± 1 during BOHB and lactate infusion, respectively. Neuroglycopenic symptoms decreased from 11 ± 2 to 3 ± 1 during both series of experiments. Infusion of BOHB and lactate-reduced responses for all counterregulatory hormones, the reduction being the greatest for epinephrine (∼57 and 73%, during BOHB and lactate infusion, respectively) and least for cortisol (7sim;28 and 29%, respectively). These results indicate that under certain clinical conditions, BOHB and lactate may substitute for glucose as a fuel for the brain and alter physiological responses to hypoglycemia.

Effect of Aging on Glucose Homeostasis: Accelerated Deterioration of Beta Cell Function in Individuals with Impaired Glucose Tolerance

OBJECTIVE—To examine the effect of aging on insulin secretion (first- and second-phase insulin release) and insulin sensitivity in people with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS—First- and second-phase insulin secretion and insulin sensitivity were assessed in hyperglycemic clamp experiments in 266 individuals with NGT and 130 individuals with IGT, ranging in age from ∼20 to ∼70 years. Changes in β-cell function were compared using the disposition index to adjust for differences in insulin sensitivity. RESULTS—As expected, both phases of insulin release and insulin sensitivity were reduced in individuals with IGT (all P < 0.01). Insulin sensitivity was not independently correlated with age in either group. In people with NGT, the disposition index for first- and second-phase insulin release decreased similarly at a rate of ∼0.7% per year. In people with IGT, the disposition indexes for first- and second-phase insulin release decreased at greater rates (∼2.2 and 1.4% per year, P = 0.002 and 0.009, respectively, vs. NGT), with the decrease in first phase being greater than that of second phase (P = 0.025). CONCLUSIONS—Insulin secretion (both first and second phase) normally decreases at a rate of ∼0.7% per year with aging; this decrease in β-cell function is accelerated about two-fold in people with impaired glucose tolerance—first phase to a greater extent than second phase. Finally, aging per se has no effect on insulin sensitivity independent of changes in body composition.