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Purpose of ReviewThiazolidinediones (TZDs) are the only pharmacologic agents that specifically treat insulin resistance. The beneficial effects of TZDs on the cardiovascular risk factors associated with insulin resistance have been well documented. TZD use has been limited because of concern about safety issues and side effects.Recent FindingsRecent studies indicate that cardiovascular toxicity with rosiglitazone and increase in bladder cancer with pioglitazone are no longer significant issues. There are new data which show that pioglitazone treatment reduces myocardial infarctions and ischemic strokes. New data concerning TZD-mediated edema, congestive heart failure, and bone fractures improves the clinician’s ability to select patients that will have minimal significant side effects.SummaryThiazolidinediones are now generic and less costly than pharmaceutical company–promoted therapies. Better understanding of the side effects coupled with clear benefits on the components of the insulin resistance syndrome should promote TZD use in treating patients with type 2 diabetes.

Purpose of ReviewKetosis-prone diabetes or Flatbush diabetes has been widely recognized as a clinical entity since 1984. Most of the early clinical studies focused on African American or Afro-Caribbean individuals. It is now being recognized as an important clinical entity in sub-Saharan Africans, Asian and Indian populations, and Hispanic populations. Major questions remain as to its pathogenesis and whether it is a unique type of diabetes or a subset of more severe type 2 diabetes with greater loss of insulin action in target tissues. This review summarizes the main clinical and mechanistic studies to improve the understanding of ketosis-prone (Flatbush) diabetes.Recent FindingsLittle data are available on the magnitude of KPD in the different susceptible populations. It is relatively common in black populations. KPD is defined as a syndrome in which diabetes commences with ketoacidosis in individuals who are GAD and anti-islet cell antibody negative and have no known precipitating causes. The patients present during middle age, are overweight or mildly obese, and in many reports are more likely to be male. After intensive initial insulin therapy, many patients become insulin independent and can be well controlled on diet alone or diet plus oral medications.SummaryThe clinical course of KPD is like that of patients with type 2 diabetes rather than that of type 1 diabetes. Little differences are found in the clinical characteristics and clinical outcomes between patients presenting with KPD and those presenting with severe hyperglycemia with no ketoacidosis. The mechanisms responsible for the development of ketosis-prone diabetes as well its remission remain unknown.

At the end of 11 years of treatment, the reduction in vascular complications with insulin was no greater than that with sulfonylureas (9). [...] there is not a long-term randomized controlled trial that shows improved outcomes in insulin-treated type 2 diabetic patients compared with other treatments.\\n As shown in Table 2, clinical outcomes in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI-2D) trial were shown to be better in patients with type 2 diabetes and coronary heart disease undergoing coronary bypass surgery and treated with an insulin-sensitizing strategy than in patients treated with an insulin-providing strategy (38).

Several lines of evidence that support the hypothesis that visceral adipose tissue is the major contributor in causing insulin resistance and the metabolic syndrome are discussed. Moreover, several recent studies involving nondiabetic Asian Indians suggest that regional adipose tissue metabolic activity may be quantitatively different depending on the ethnic background of the individual.

New antidiabetic agents enable many patients with type 2 diabetes mellitus (T2DM) to achieve target HbA 1c levels. However, a range of factors can interfere with the ability of some patients to reach metabolic targets. This Review discusses the current therapies for patients with T2DM and assesses the relative benefits and risks of surgical treatment of overweight and obese patients with T2DM. Patients with type 2 diabetes mellitus (T2DM) are usually treated with pharmacologic agents in combination with lifestyle modification. The development of new antidiabetic agents, such as insulin analogs and incretin-based therapies, has led to treatment strategies that enable many patients with T2DM to achieve target HbA 1c levels (≤7.0%). However, many factors—including those related to the patient or the health-care provider, drug inadequacies and adverse effects—can interfere with the ability of some patients to reach metabolic targets. Clinical data from the USA indicate that HbA 1c concentration, blood pressure and serum levels of lipids in patients with T2DM are progressively decreasing toward the target goals set by the American Diabetes Association. These improvements in metabolic regulation have led to a 30–40% decrease in reported microvascular and macrovascular complications of diabetes mellitus in the USA. Gastric bypass surgery in morbidly obese individuals with T2DM leads to remission of the diabetes mellitus in the majority of patients and improvement in the rest. A major contributor to this improvement is an alteration in gastrointestinal hormone secretions. Interventional surgery might, therefore, be considered a reasonable therapeutic alternative for overweight and obese (BMI <35 kg/m²) patients with T2DM who do not respond to medical therapy. Key Points Lifestyle modification in combination with current pharmacologic therapies can achieve targets of metabolic control in many patients with type 2 diabetes mellitus (T2DM) Factors related to the patient, health-care provider and drug regime can interfere with patients reaching these targets In the USA, control of HbA 1c , blood pressure and lipid values improved during 1988–1994, and were reflected in 30–40% decreases in vascular complications in patients with T2DM Gastric bypass surgery in morbidly obese patients with T2DM causes remission of their diabetes mellitus or marked improvement in hyperglycemia within several weeks of the surgery The mechanisms by which gastric bypass surgery improves diabetes mellitus include dramatic alterations in gastrointestinal hormone secretory patterns Long-term efficacy and safety data from comparative studies are needed to evaluate gastric bypass surgery as a primary therapy for patients with T2DM and a BMI <35 kg/m 2

Is bariatric surgery as primary therapy for type 2 diabetes mellitus (T2DM) with body mass index (BMI) <35 kg/m(2) justified? Open-label studies have shown that bariatric surgery causes remission of diabetes in some patients with BMI <35 kg/m(2). All such patients treated had substantial weight loss. Diabetes remission was less likely in patients with lower BMI than those with higher BMI, in patients with longer than shorter duration and in patients with lesser than greater insulin reserve. Relapse of diabetes increases with time after surgery and weight regain. Deficiencies of data are lack of randomized long-term studies comparing risk/benefit of bariatric surgery to contemporary intensive medical therapy. Current data do not justify bariatric surgery as primary therapy for T2DM with BMI <35 kg/m(2).

Insulin replacement therapy in type 1 diabetes mellitus (T1DM) leads to peripheral hyperinsulinemia, which is associated with potentially serious metabolic complications, such as increased hypoglycemia, weight gain and postprandial hyperglucagonemia. This Review discusses adjunctive therapies to minimize these complications in patients with T1DM, with a focus on the islet amyloid polypeptide analog pramlintide. Insulin replacement therapy in type 1 diabetes mellitus (T1DM) is nonphysiologic. Hyperinsulinemia is generated in the periphery to achieve normal insulin concentrations in the liver. This mismatch results in increased hypoglycemia, increased food intake with weight gain, and insufficient regulation of postprandial glucose excursions. Islet amyloid polypeptide is a hormone synthesized in pancreatic β cells and cosecreted with insulin. Circulating islet amyloid polypeptide binds to receptors located in the hindbrain and increases satiety, delays gastric emptying and suppresses glucagon secretion. Thus, islet amyloid polypeptide complements the effects of insulin. T1DM is a state of both islet amyloid polypeptide and insulin deficiency. Pramlintide, a synthetic analog of islet amyloid polypeptide, can replace this hormone in patients with T1DM. When administered as adjunctive therapy to such patients treated with insulin, pramlintide decreases food intake and causes weight loss. Pramlintide therapy is also associated with suppression of glucagon secretion and delayed gastric emptying, both of which decrease postprandial plasma glucose excursions. Pramlintide therapy improves glycemic control and lessens weight gain. Agents that decrease intestinal carbohydrate digestion (alpha-glucosidase inhibitors) or decrease insulin resistance (metformin) might be alternative adjunctive therapies in T1DM, though its benefits are marginally supported by clinical data. Key Points Islet amyloid polypeptide is a hormone that is cosecreted with insulin from pancreatic β cells Islet amyloid polypeptide binds to receptors located in the hindbrain and its effects are mediated through the central nervous system Pramlintide is a synthetic analog of islet amyloid polypeptide that does not aggregate but has the same biological activity as human islet amyloid polypeptide Administration of pramlintide to patients with type 1 diabetes mellitus (T1DM) increases satiety, reduces food intake, decreases body weight, delays gastric emptying and decreases glucagon secretion The administration of pramlintide to patients with T1DM or insulin-treated type 2 diabetes mellitus before meals is associated with decreased HbA 1c concentrations and decreased body weight Other potential adjunctive therapies for patients with T1DM are agents that inhibit carbohydrate digestion (alpha-glucosidase inhibitors) or agents that decrease insulin resistance (metformin)

This report presents an algorithm to assist primary care physicians, endocrinologists, and others in the management of adult, nonpregnant patients with type 2 diabetes mellitus. In order to minimize the risk of diabetes-related complications, the goal of therapy is to achieve a hemoglobin A1c (A1C) of 6.5% or less, with recognition of the need for individualization to minimize the risks of hypoglycemia. We provide therapeutic pathways stratified on the basis of current levels of A1C, whether the patient is receiving treatment or is drug naïve. We consider monotherapy, dual therapy, and triple therapy, including 8 major classes of medications (biguanides, dipeptidyl-peptidase-4 inhibitors, incretin mimetics, thiazolidinediones, alpha-glucosidase inhibitors, sulfonylureas, meglitinides, and bile acid sequestrants) and insulin therapy (basal, premixed, and multiple daily injections), with or without orally administered medications. We prioritize choices of medications according to safety, risk of hypoglycemia, efficacy, simplicity, anticipated degree of patient adherence, and cost of medications. We recommend only combinations of medications approved by the US Food and Drug Administration that provide complementary mechanisms of action. It is essential to monitor therapy with A1C and self-monitoring of blood glucose and to adjust or advance therapy frequently (every 2 to 3 months) if the appropriate goal for each patient has not been achieved. We provide a flow-chart and table summarizing the major considerations. This algorithm represents a consensus of 14 highly experienced clinicians, clinical researchers, practitioners, and academicians and is based on the American Association of Clinical Endocrinologists/American College of Endocrinology Diabetes Guidelines and the recent medical literature.

A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone. A total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500-2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio. After 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was -0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (-0.91 mg/dL and -7.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally well-tolerated with a comparable safety profile to metformin-placebo. Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes.