Hyperglycemia and Obesity

The link between hyperglycemia and obesity is well established and the prevalence of both is increasing worldwide. WHO data suggest that 13% of adults ≥18 years of age are obese while the number of people diagnosed with diabetes has increased more than 3-fold in the last 40 years.

Prospective observational data from a 16-year follow-up show that overweight or obesity is the single most important predictor for the development of type 2 diabetes mellitus (T2DM).

On the other hand, the most common tools used to measure obesity, such as body mass index (BMI), waist-hip ratio and waist circumference, are positively associated with the development of T2DM in people with prediabetes or intolerance. to glucose (ITG).

The key mechanism linking hyperglycemia and obesity is insulin resistance.

It is believed that in this process, the role of adipose tissue is fundamental. Adipose tissue increases the circulation of non-esterified fatty acids (NEFA), leptin and adipocytokines, which act synergistically to promote a pro-inflammatory state and insulin resistance.

Non-esterified fatty acids (NEFA) affect insulin secretion, but prolonged increases in plasma levels of non-esterified fatty acids (NEFA) were found to abrogate the effect of hyperglycemia on insulin secretion and reduce insulin sensitivity. insulin in men with obesity. There is also thought to be a direct effect on pancreatic β cell function resulting from glucolipotoxicity in patients with obesity.

Diabetes is the direct cause of 1 in 9 deaths in adults aged 20 to 79 years. Obesity is the most modifiable risk factor for the development of hyperglycemia, and although the prevalence of hyperglycemia in the nondiabetic range worldwide is not well established, it is clear that obesity is the predominant predictor of ITG.

People with diabetes and obesity develop more cardiovascular diseases (CVD), kidney and neuropathic complications than those who are not obese.

The effects of obesity on the development of chronic kidney disease (CKD), CVD, obstructive sleep apnea, non-alcoholic fatty liver disease and cancer are well known. These results may not necessarily be enhanced by insulin resistance or hyperglycemia. However, the presence of hyperglycemia increases the risk of developing these complications.

More recently, people with obesity who developed severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2; Coronavirus 2019 (COVID-19)) were found to have significantly higher mortality rates when other risk factors were taken into account. acquaintances.

Obesity is also independently associated with the development of CVD, neuropathy, and CKD in people with type 1 diabetes mellitus (T1DM) or T2DM. Furthermore, obesity appears to be a significant risk factor for retinopathy in people with DM1.

Weight loss appears to lead to better glycemic control.

The weight loss needed to significantly improve glycemic control could be as little as 5% of initial body weight while significant weight loss within 6 years of T2DM diagnosis can lead to remission.

In the DiRECT study, incorporating meal replacement therapy and frequent clinical contact, almost half of the people entering the study lost weight, with a mean loss of 10 kg in the intervention group at 1 year.

In one group, remission rates were observed depending on the magnitude of weight loss: people who lost more weight had higher remission rates. This may occur as a result of reduced insulin resistance and loss of hepatic and pancreatic fat, leading to improved β-cell function and insulin sensitivity. However, longer-term follow-up of people with T2DM and weight loss has not shown improved survival.

A prospective analysis of overweight people with T2DM examined mortality rates at 9 years and showed that people who intentionally attempted to lose weight had a lower risk of all-cause mortality, regardless of whether they had lost weight, while those who lost weight involuntarily had a higher risk of mortality.

Involuntary weight loss could be pathologically caused by another disease or illness and not be correlated with a reduction in adipose tissue but rather in skeletal mass, or it could be related to uncontrolled diabetes. Limitations of most studies examining whether loss can provide survival benefits are potential confounding factors, such as age, multiple health conditions, and duration of diabetes.

Lifestyle management is the first-line management for patients with a newly diagnosed diabetes.

Participants in the DiRECT trial participated in an intensive weight management program, in which they received total dietary replacement (825–853 kcal/day) with graded reintroduction of foods and support to maintain weight loss. This led to diabetes remission in almost half of the participants.

Other studies have shown that structured weight loss programs using a low-calorie diet are beneficial in improving glycemic control in people with T2DM who are overweight or obese. It has been proven that a low-calorie Mediterranean Diet (1,500 kcal/day for women and 1,800 kcal/day for men), rich in vegetables and whole grains and low in red meat, is associated with a greater reduction in glycated hemoglobin (HbA1c) and higher diabetes remission rates compared to low-fat diets.

On the other hand, a study that examined the effect of the short-term use of very low-calorie diets (330 cal/day) followed 40 days later by an isocaloric diet showed that those who followed this scheme experienced a reduction in fasting blood glucose of almost 90 mg/dl, which persisted after 40 days. The study suggested that there are independent mechanisms of weight loss in those following very low-calorie diets. Diets can improve glycemic control. An important concern is the possibility of weight regain and whether such low-calorie diets can be adhered to in the long term.

Physical activity has also been shown to improve insulin sensitivity.

Even a single session of physical activity can improve short-term insulin-stimulated glucose uptake, although sensitivity disappears quickly when exercise stops. Regular exercise, regardless of weight loss, has also been found to improve insulin sensitivity.

The Finnish Diabetes Prevention study evaluated how lifestyle might affect people with STIs. During a 4-year follow-up, people who achieved moderate-high levels of long-term physical activity were almost 50% less likely to develop T2DM when adjusted for changes in diet and body weight, compared with those who reached lower levels.

Similarly, the result of the CChinese Da Qing Diabetes study on diabetes prevention in nearly 600 people with ITG over 30 years showed that people who underwent an intensive weight loss and improved lifestyle program there was a delay average in the development of T2DM of almost 4 years, along with a lower burden of CVD and cardiovascular death.

The Prevention Diabetes Study compared metformin with an intensive weight loss program and found that lifestyle changes were more effective in preventing or delaying the development of T2DM in the presence of ITG than metformin alone (58% vs. 31%). The lifestyle intervention included a goal of at least 7% weight loss and 150 min of physical activity per week.

Diet and physical activity are two pillars of managing hyperglycemia in people with obesity.

It is clear that lifestyle intervention, especially in the early stages of the condition, can prevent progression from ITG to T2DM, induce remission in people with T2DM, or at least lead to better glycemic control.

Creating and maintaining lifestyle interventions for clinicians and patients can be difficult. It has been shown that the improvement in glycemic control due to a low-calorie diet and increased physical activity is not only mediated by weight loss. However, when weight loss is achieved, there appears to be better cardiovascular outcomes, although this appears to require a minimum weight loss of 5%.

Intensive interventions require frequent contact with health professionals and a commitment to adherence to calorie restrictions and regular exercise. However, it remains to be seen whether this can be replicated and maintained on a population scale.

There are currently several pharmacological therapies available to treat hyperglycemia in people with T2DM. A major challenge is managing the balance between adverse effects on weight and positive effects on glycemia.

> Drugs that induce weight gain

Many older agents used in the treatment of T2DM induce weight gain. Sulfonylureas , which are commonly used in patients with T2DM, show good efficacy in lowering glucose and were previously used as second-line medications after metformin. A major concern is the increased risk of hypoglycemia , especially in older people. By virtue of pancreatic insulin release not dependent on glucose stimulation, it also causes weight gain . The evidence on whether weight gain translates into an increased risk of CVD and subsequent morbidity and mortality is unclear.

Pioglitazone is a thiazolidinedione that acts through its agonist action of the peroxisome proliferator-activated receptor - γ . It is not commonly used due to possible adverse effects around fluid retention, heart failure, and increased risk of fractures in postmenopausal women. Although the action of pioglitazone appears to improve insulin sensitivity, it causes significant weight gain. Therefore, in most guidelines it is indicated as a third or perhaps fourth line medication.

Insulin therapy is commonly necessary for people with T2DM who have already exhausted β-cell function after decades of diabetes.

It is one of the most used therapies in the treatment of DM2 and may have to be used in people with intolerance to other medications, or who have not achieved adequate levels of glycemic control. Insulin is an anabolic hormone and often causes significant weight gain (~1.56–5.75 kg), especially in obese people. Therefore, relatively high doses of insulin may be required to achieve adequate glycemic efficacy.

A meta-analysis of randomized controlled trials found that premixed insulin regimens were associated with greater weight gain compared with long-acting insulin regimens such as glargine or detemir. On the other hand, weight gain is positively associated with insulin dose.

In terms of minimizing weight gain, regimens using basal insulin rather than prandial or biphasic insulin may be better, although the latter may lead to better glucose control. One of the mechanisms by which insulin therapy induces weight gain is thought to be direct effects on metabolism, such as stimulation of triglyceride production, reduction of glycosuria, and change in body tissue composition. adipose and lean mass.

> Medications that induce weight loss or are weight neutral

Metformin has been the first-line treatment for T2DM for many years . Improves blood glucose with low risk of hypoglycemia. Most studies suggest that metformin can induce modest weight loss, even in people with obesity but without diabetes. The mechanisms underlying metformin-induced weight loss are not well understood but are likely multifactorial.

There is evidence that metformin has hypothalamic effects on satiety by modulating insulin and leptin sensitivity. On the other hand, combining metformin with insulin could mitigate some of the weight gain commonly seen with insulin regimens by itself. There is also evidence that combining metformin with a sulfonylurea may reduce the weight gain typically associated with sulfonylurea use.

Dipeptidylpeptidase-4 inhibitors ( DPP-4i) are another class of drugs used in therapy for T2DM. They block the breakdown of endogenous glucagon-like peptide 1 (GLP-1) and raise its physiological levels. They cause few side effects. The increased risk of pancreatitis that has always been a concern is very small in recent studies. The DPP-4 also appears to maintain a neutral weight. However, they are not very effective in terms of glycemic control and have not been shown to protect against cardiovascular diseases. A DPP-4i, linagliptin, is one of the few oral agents that can be used in severe chronic kidney disease and does not cause hypoglycemia.

Sodium-glucose transporter-2 inhibitors ( SLGT-2i) are an important group of medications for the management of hyperglycemia in T2DM. As a result, the use of SLGT-2is is often associated with a weight loss of about 2 kg as a result of increased renal glucose loss and reduced calorie absorption. Despite there being a higher risk of urinary and genital tract infections , SLGT-2is show a good reduction in HbA1c depending on the level of kidney function. SGLT-2 reduces blood pressure . These positive benefits on blood pressure, weight, blood glucose, and other metabolic effects could be responsible for the cardiovascular and renal benefits observed with these agents in people with and without diabetes.

The National Institute of Health and Care Excellence (NICE) has updated its diabetes recommendations to encourage the use of SLGT-2 as a first or second line treatment. Treatment with SLGT-2i is indicated for patients at high risk of CVD, established CVD or kidney disease. People without diabetes but with heart failure or chronic kidney disease can also receive SLGT-2is. A meta-analysis of studies using SGLT-2is in patients with obesity and overweight but without diabetes showed a statistically significant reduction in body weight of 1.42 kg (BMI –0.47 kg/m2).

GLP-1 analogs significantly reduce glucose and increase weight loss. Although oral formulations are available, once/week subcutaneous preparations appear to be most effective.

Semaglutide is an injection given 1/week and was associated with significant weight loss: 15% reduction in body weight over 68 weeks . It is also associated with greater glycemic efficacy compared to other antidiabetic agents, such as sitagliptin, liraglutide, and dulaglutide. The main side effects are gastrointestinal and, rarely, pancreatitis. GLP-1 analogs also achieve better cardiorenal results, although not as potent as SGLT-2. GLP-1 analogs have also been used to promote weight loss in patients without diabetes.

Tirzepatide is a novel polypeptide that acts on both the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide receptor . A larger study assigned 2,500 participants to 1 of 4 groups (placebo, 5 mg, 10 mg, or 15 mg of tirzepatide) for 72 weeks. The mean BMI at baseline was 38 kg/m2, with a mean body weight of 104.8 kg.

The medication was associated with significant weight loss; half of the patients who received the weekly dose of 10 mg and 57% of those who received 15 mg lost more than 20% of their total body weight.

Furthermore, at baseline, 97% of all groups had prediabetes. At the end of the study, 95.3% of the tirzepatide-treated groups reverted to normoglycemia compared with 62% in the placebo group. The relatively high rate of normoglycemia achieved in the placebo group suggests that there is some benefit from simply participating in a trial and having more contact with health professionals, but the finding that almost all patients achieved normoglycemia in the placebo groups of treatment is certainly encouraging.

Alpha-glucosidase inhibitors such as acarbose have been used for several years but in the UK their use is rare due to their gastrointestinal side effects and contraindications in kidney and liver diseases. A meta-analysis comparing acarbose with DPP-4 found that, although the effect on glycemic control was similar, acarbose was associated with greater weight loss but a higher rate of withdrawal, resulting primarily from gastrointestinal side effects. In a selected group of patients with obesity, the use of acarbose could be useful if the drug is tolerated, especially if other medications are contraindicated.

> Surgical management of obesity and its effect on hyperglycemia

It is well established that bariatric surgery significantly improves blood glucose and often induces diabetes remission.

There has been debate about whether there are other non-surgical weight loss strategies that are helpful. Bray et al discussed the effects of calorie restriction and exercise and explored the concept of “relapse” after intentional weight loss.

When the hypothalamus detects weight loss, it experiences a change in pro-appetite hormones , suggesting that to maintain weight loss, maintaining diet and exercise will help throughout life. Long-term follow-up of patients undergoing bariatric surgery suggests that weight loss is maintained.

Patients in a large Swedish study who underwent gastric bypass lost 32% of their weight after 1-2 years and 25% from baseline after 10 years. There was also a significant mortality benefit for patients who underwent any form of bariatric surgery compared to the control group, who received standard care.

It is likely that the mechanisms that improve glycemic control related to increased levels of circulating satiety hormones, such as peptide YY and GLP-1, there is a mechanical effect of shorter food transit time, which serves to amplify these signals. Furthermore, better glycemic control is achieved due to higher levels of circulating insulin after bariatric surgery, and patients are at risk for reactive hypoglycemia after meals.

A randomized controlled trial in which patients with BMI >35 kg/m2 were selected to receive conventional medical care or undergo bariatric surgery analyzed the rate of diabetes remission. No patients in the medical therapy group achieved diabetes remission after 2 years. In contrast, 75% of patients who underwent gastric bypass achieved diabetes remission.

Buchwald et al. found that 83.8% of patients undergoing gastric bypass and 98% of patients undergoing biliopancreatic diversion achieved complete resolution of diabetes .

In summary, bariatric surgery is an effective method to treat both hyperglycemia and obesity. There is increasing evidence that weight loss can be maintained over a longer period of time.

Modern bariatric surgery techniques have improved the safety of the procedure, with perioperative mortality rates <0.2%. Some evidence has now emerged to suggest that surgery has psychological effects when patients make food choices. A cohort of patients may not be suitable for surgical intervention or may not want to opt for it, but bariatric surgery promises an avenue to improve hyperglycemia in severely obese individuals.

Obesity and hyperglycemia are common companions.

Obesity worsens insulin resistance, induces β-cell exhaustion, and predisposes to the development of T2DM.

Treatment of hyperglycemia in patients with obesity requires an approach that minimizes weight gain and focuses on weight loss. Although diet and exercise have been shown to have considerable benefits, patients need to maintain these activities to reap cardiometabolic benefits over time.

Pharmacotherapy with SLGT-2is and GLP-1 analogs demonstrates significant benefits for weight loss, improved glucose control, and cardiorenal benefits. Therefore, it is necessary to individualize diabetes therapy based on weight and recognized in national and international guidelines. Bariatric surgery has also demonstrated considerable benefits for severely obese patients but requires careful selection.